Pyridopyrazines and derivatives thereof as ALK and c-Met inhibitors

ABSTRACT

The present invention provides a compound of Formula I 
                         
or a pharmaceutically acceptable salt form thereof, wherein A, L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and X are as defined herein. The compounds of Formula I have ALK and/or c-Met inhibitory activity, and may be used to treat ALK- or c-Met-mediated disorders or conditions.

BACKGROUND OF THE INVENTION

Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning receptortyrosine kinase, which belongs to the insulin receptor subfamily. Themost abundant expression of ALK occurs in the neonatal brain, suggestinga possible role for ALK in brain development (Duyster, J. et al.,Oncogene, 2001, 20, 5623-5637).

ALK is also implicated in the progression of certain tumors. Forexample, approximately sixty percent of anaplastic large cell lymphomas(ALCL) are associated with a chromosome mutation that generates a fusionprotein consisting of nucleophosmin (NMP) and the intracellular domainof ALK. (Armitage, J. O. et al., Cancer: Principle and Practice ofOncology, 6^(th) edition, 2001, 2256-2316; Kutok J. L. & Aster J. C., J.Clin. Oncol., 2002, 20, 3691-3702). This mutant protein, NMP-ALK,possesses a constitutively active tyrosine kinase domain that isresponsible for its oncogenic property through activation of downstreameffectors. (Falini, B. et al., Blood, 1999, 94, 3509-3515; Morris, S. W.et al., Brit. J. Haematol., 2001, 113, 275-295; Duyster et al.; Kutok &Aster). Experimental data have demonstrated that the aberrant expressionof constitutively active ALK is directly implicated in the pathogenesisof ALCL and that inhibition of ALK can markedly impair the growth ofALK+ lymphoma cells (Kuefer, Mu et al. Blood, 1997, 90, 2901-2910; Bai,R. Y. et al., Mol. Cell. Biol., 1998, 18, 6951-6961; Bai, R. Y. et al.,Blood, 2000, 96, 4319-4327; Ergin, M. et al., Exp. Hematol., 2001, 29,1082-1090; Slupianek, A. et al., Cancer Res., 2001, 61, 2194-2199;Turturro, F. et al., Clin. Cancer Res., 2002, 8, 240-245). Theconstitutively activated chimeric ALK has also been demonstrated inabout 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growingsarcoma that mainly affects children and young adults. (Lawrence, B. etal., Am. J. Pathol., 2000, 157, 377-384; Duyster et al.).

In addition, ALK and its putative ligand, pleiotrophin, areoverexpressed in human glioblastomas (Stoica, G. et al., J. Biol. Chem.,2001, 276, 16772-16779). In mouse studies, depletion of ALK reducedglioblastoma tumor growth and prolonged animal survival (Powers, C. etal., J. Biol. Chem., 2002, 277, 14153-14158; Mentlein, R. et al, J.Neurochem., 2002, 83, 747-753).

It is possible that an ALK inhibitor would either permit durable cureswhen combined with current chemotherapy for ALCL, IMT, or glioblastoma,or be used as a single therapeutic agent in a maintenance role toprevent cancer recurrence in those patients. Various ALK inhibitors havebeen reported, including indazoloisoquinolines (WO 2005/009389),thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines(WO 2005080393), and pyrimidinediamines (WO 2005/016894).

c-Met is a member of the tyrosine kinase growth factor receptor family.c-Met expression occurs in endothelial, epithelial, and mesenchymalcells. c-Met binding to the endogenous ligand, hepatocyte growth factor(HGF), promotes cell migration, proliferation, and invasion.

c-Met is implicated in the progression of certain tumors. c-Metoverexpression has been shown in numerous tumor types including colon,breast, renal, lung, hemangiomas, squamous cell myeloid leukemia,melanomas, glioblastomas, and astrocytomas. (Maulik et al., Cytokine &Growth Factor Reviews, 2002, 13, 41-59; Funakoshi et al., ClinicaChimica Acta, 2003, 1-23; Longati et al., Curr. Drug Targets, 2001, 2,41-55). Activation of tumor cell c-Met receptors enhances tumor cellproliferation, invasion/metastasis, and resistance to apoptosis andcytotoxic therapies.

It is possible that a c-Met inhibitor would have potent anti-tumoreffects in many cancers. Various c-Met inhibitors have been reported,including aminoheteroaryl compounds (WO 2004/076412; WO 2005/082411; US2005/0009840), 5-6 bicyclic heterocycles (WO 2005/028475), monocyclicheterocycles (US 2005/0245530), bicyclic heterocycles (US 2005/0239820),triazolotriazine compounds (WO 2005/010005; US 2005/0075340),triarylimidazoles (US 2005/0085473), indolinone hydrazides (WO2005/005378), tetracyclic compounds (WO 2005/004808), imidazolederivatives (WO 2005/040154), quinolines and quinazolines (WO2005/030140), and quinolinoxynaphthalenes (WO 2005/070891). (See alsoSattler, M., et al., Cancer Res., 2003, 63, 5462-5469; Christensen, J.G., et al., Cancer Res., 2003, 63, 7345-7355).

A need exists for ALK and c-Met inhibitors for use as pharmaceuticalagents.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I

or a pharmaceutically acceptable salt form thereof, wherein A, L¹, R¹,R², R³, R⁴, R⁵, R⁶, and X are as defined herein.

The compounds of Formula I have ALK and/or c-Met inhibitory activity,and may be used to treat ALK- or c-Met-mediated disorders or conditions.

The present invention further provides a pharmaceutical compositioncomprising at least one compound of the present invention together withat least one pharmaceutically acceptable carrier, diluent, or excipienttherefor.

In another aspect, the present invention provides a method of treating asubject suffering from an ALK- or c-Met-mediated disorder or conditioncomprising: administering to the subject the pharmaceutical compositionof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

As used herein, the following terms have the meanings ascribed to themunless specified otherwise.

“Alkyl” or “alkyl group” includes both straight and branched chainaliphatic hydrocarbon groups. Examples of straight-chain alkyl groupsinclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Examples ofbranched-chain alkyl groups include, but are not limited to, isopropyl,tert-butyl, isobutyl, etc.

The term “C_(x-y)” indicates the number of carbon atoms in a group. Forexample, a “C₁₋₆-alkyl” is an alkyl group having from one (1) to six (6)carbon atoms. In some instances, x=0, i.e., “C_(0-y)”. The term“C_(0-y)” indicates that the group may be absent or present, and ifpresent, defines the number of carbon atoms in the group. For example,“C₀₋₆-alkyl” indicates that an alkyl group may be absent (x=0) orpresent (x=1-6), and if present contains from one (1) to six (6). carbonatoms. For example, “—C₀₋₆-alkyl-C(═O)—C₀₋₆-alkyl-” includes —C(═O)—,—C₁₋₆-alkyl-C(═O)—, and —C₁₋₆-alkyl-C(═O)—C₁₋₆-alkyl-. Examples of—C₀₋₆-alkyl-C(═O)—C₀₋₆-alkyl- include, but are not limited to, —C(═O),—CH₂CH₂—C(═O), and —CH(CH₃)CH₂CH₂—C(═O)—CH₂—.

“Alkenyl” or “alkenyl group” includes straight and branched chainunsaturated alkyl groups which have two (2) or more carbon atoms and atleast one double bond. Examples include, but are not limited to,ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.

“Alkynyl” or “alkynyl group” includes straight and branched chainunsaturated alkyl groups which have two (2) or more carbon atoms and atleast one triple bond. Examples include, but are not limited to,ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.

“Haloalkyl” or “haloalkyl group” refers to alkyl groups in which one ormore hydrogen atoms are replaced by halogen atoms. Haloalkyl includesboth saturated alkyl groups and unsaturated alkenyl and alkynyl groups,such as for example —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃,—CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂,—CI═CH₂, —C≡C—CF₃, —CHFCH₂CH₃ and —CHFCH₂CF₃.

“Halogen” includes fluorine, chlorine, bromine and iodine atoms.

“Pseudohalogen” refers to —OCN, —SCN, —CF₃, and —CN.

“Cycloalkyl” or “cycloalkyl group” includes monocyclic, bicyclic, andtricyclic non-aromatic carbocyclic rings, which may be saturated orunsaturated. Examples include, but are not limited to, cyclopropyl,cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, norbornyl, and norbornenyl.

A cycloalkyl group can also include ring systems substituted on ringcarbons with one or more —OH functional groups (which may furthertautomerize to give a ring C═O group).

“Heterocycloalkyl” or “heterocycloalkyl group” includes 3-15 memberedmonocyclic, bicyclic, and tricyclic non-aromatic rings, which may besaturated or unsaturated, and which contain, in addition to carbonatoms, at least one heteroatom, such as nitrogen, oxygen or sulfur.Examples include, but are not limited to, tetrahydrofuranyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl,morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl,homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide,pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl,homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-5-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane,8-oxa-3-aza-bicyclo[3.2.1]octane, 3,8-diaza-bicyclo[3.2.1]octane,2,5-diaza-bicyclo[2.2.1]heptane, 3,8-diaza-bicyclo[3.2.1]octane,3,9-diaza-bicyclo[4.2.1]nonane and 2,6-diaza-bicyclo[3.2.2]nonane.

Unless otherwise indicated, the foregoing heterocycloalkyl groups can beC— attached or N-attached where such is possible and results in thecreation of a stable structure. For example, piperidinyl can bepiperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).

A heterocycloalkyl group can also include ring systems substituted onring carbons with one or more —OH functional groups (which may furthertautomerize to give a ring C═O group) and/or substituted on a ringsulfur atom by one (1) or two (2) oxygen atoms to give S═O or SO₂groups, respectively.

“Aryl” or “aryl group” includes phenyl and 9-15 membered bicyclic ortricyclic hydrocarbon ring systems in which at least one of the rings isaromatic. Examples include, but are not limited to, naphthyl, indanyl,1,2,3,4-tetrahydronaphthalenyl, and6,7,8,9-tetrahydro-5H-benzocycloheptenyl.

An aryl group can also include ring systems substituted on ring carbonswith one or more —OH functional groups (which may further tautomerize togive a ring C═O group).

“Heteroaryl” or “heteroaryl group” includes (a) 5 and 6 memberedmonocyclic aromatic rings, which contain, in addition to carbon atom(s),at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b)8-15 membered bicyclic and tricyclic rings, which contain, in additionto carbon atoms, at least one heteroatom, such as nitrogen, oxygen orsulfur, and in which at least one of the rings is aromatic. Examplesinclude, but are not limited to, 2,3-dihydrobenzofuranyl,1,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl,2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl,pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3-thienyl, tetrazolyl,thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl,pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl,naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl,benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl,benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl,benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl,indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl,quinoxalinyl, isoindolyl, and isoquinolinyl.

A heteroaryl group can also include ring systems substituted on ringcarbons with one or more —OH functional groups (which may furthertautomerize to give a ring C═O group) and/or substituted on a ringsulfur atom by one (1) or two (2) oxygen atoms to give S═O or SO₂groups, respectively.

“Linker” or “linker group” refers to a bond, atom, or group of atomsthat connects other atoms or groups of atoms within a molecule. Forexample, L¹ is a linker group that connects the groups A and R¹ in acompound of Formula I (A-L¹-R¹). Linker groups are identified herein asan atom or group of atoms between two dashed lines (—). For example, anoxygen atom linker is identified herein as —O—. As used herein, nodirectionality is intended in the representation of asymmetricallinkers. Therefore, “—C₁₋₆-alkyl-C(═O)—” is equivalent to“—C(═O)—C₁₋₆-alkyl-” and “—C₁₋₆-alkyl-C(═O)O—” is equivalent to“—OC(═O)—C₁₋₆-alkyl-.” For example, the A and R¹ groups may be connectedby the asymmetrical linker, —C₁₋₆-alkyl-C(═O)—, in either of thefollowing manners: A-C₁₋₆-alkyl-C(═O)—R¹ or A-C(═O)—C₁₋₆-alkyl-R¹.

“Chemically stable” or “stable” refers to a compound that issufficiently robust to be isolated to a useful degree of purity from areaction mixture, and then incorporated into a pharmaceuticalcomposition. The present invention is directed only to stable compounds.

“Pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

When lists of alternative substituents include members which, owing tovalency requirements, chemical stability, or other reasons, cannot beused to substitute a particular group, the list is intended to be readin context to include those members of the list that are suitable forsubstituting the particular group. For example, those of ordinary skillin the art will appreciate that if G¹ is a bond, then L² and L³ shouldnot both be —O—, since peroxides are not chemically stable.

“Pharmaceutically acceptable” refers to physiologically tolerablematerials, which do not typically produce an allergic or other untowardreaction, such as gastric upset, dizziness and the like, whenadministered to a mammal.

“Therapeutically effective amount” refers to an amount of a compound, ora pharmaceutically acceptable salt thereof, sufficient to inhibit, halt,or cause an improvement in a disorder or condition being treated in aparticular subject or subject population. For example in a human orother mammal, a therapeutically effective amount can be determinedexperimentally in a laboratory or clinical setting, or may be the amountrequired by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

It should be appreciated that determination of proper dosage forms,dosage amounts, and routes of administration is within the level ofordinary skill in the pharmaceutical and medical arts, and is describedbelow.

“Subject” refers to a member of the class Mammalia. Examples of mammalsinclude, without limitation, humans, primates, chimpanzees, rodents,mice, rats, rabbits, horses, livestock, dogs, cats, sheep, and cows.

“Treatment” refers to the acute or prophylactic diminishment oralleviation of at least one symptom or characteristic associated orcaused by a disorder being treated. For example, treatment can includediminishment of several symptoms of a disorder or complete eradicationof a disorder.

“Administering” refers to the method of contacting a compound with asubject. Modes of “administering” include, but are not limited to,methods that involve contacting the compound intravenously,intraperitoneally, intranasally, transdermally, topically, viaimplantation, subcutaneously, parentally, intramuscularly, orally,systemically, and via adsorption.

II. Compounds

In one embodiment, the present invention provides a compound of FormulaI

or a pharmaceutically acceptable salt form thereof,wherein:

A is chosen from N and CH;

X is chosen from -L²G¹L³G²L⁴R⁷ and R⁸;

L¹ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₆-alkyl-, —C₂₋₆-alkenyl-, or—C₂₋₆-alkynyl-;

R¹ is an optionally mono- or polysubstituted group chosen from aryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl,

-   -   wherein the substituents may be identical or different and are        chosen from halogen, —NO₂, —OR²⁰, —C(═O)R²⁰, —C(═O)OR²⁰,        —C(═O)NR²⁰R²¹, —NR²⁰R²¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, aryl,        heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen,        —S(═O)_(n)R²⁰, —S(═O)₂NR²⁰R²¹, —OCH₂F, —OCHF₂, —OCF₃, —NHOH,        —OC(═O)R²⁰, —OC(═O)NR²⁰R²¹, —NR²⁰C(═O)R²¹, —NR²⁰C(═O)OR²¹, and        —SCF₃;

R² and R³ are independently chosen from H, OH, and C₁₋₆-alkyl, or R² andR³ together form a carbonyl group;

R⁴ and R⁵ are independently chosen from H and C₁₋₆-alkyl, or R⁴ and R⁵together form a carbonyl group, or one of R⁴ and R⁵ forms a double bondwith R⁶;

R⁶ is chosen from H and C₁₋₆-alkyl, or R⁶ forms a double bond with R⁴ orR⁵;

L² is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR³⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR³⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-, or—C₂₋₃-alkynyl-;

G¹ is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl,

-   -   wherein the substituents may be identical or different and are        chosen from halogen, —NO₂, —OR⁴⁰, —C(═O)R⁴⁰, —C(═O)OR⁴⁰,        —C(═O)NR⁴⁰R⁴¹, —NR⁴⁰R⁴¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, aryl,        heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen,        —S(═O)_(n)R⁴⁰, —S(═O)₂NR⁴⁰R⁴¹, —OCH₂F, —OCHF₂, —OCF₃, —NHOH,        —OC(═O)R⁴⁰, —OC(═O)NR⁴⁰R⁴¹, —NR⁴⁰C(═O)R⁴¹, —NR⁴⁰C(═O)OR⁴¹, and        —SCF₃;

L³ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O),—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-, or—C₂₋₃-alkynyl-;

G² is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl,

-   -   wherein the substituents may be identical or different and are        chosen from halogen, —NO₂, —OR⁶⁰, —C(═O)R⁶⁰, —C(═O)OR⁶⁰,        —C(═O)NR⁶⁰R⁶¹, —NR⁶⁰R⁶¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, aryl,        heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen,        —S(═O)_(n)R⁶⁰, —S(═O)₂NR⁶⁰R⁶¹, —OCH₂F, —OCHF₂, —OCF₃, —NHOH,        —OC(═O)R⁶⁰, —OC(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)OR⁶¹, —NR⁶⁰C(═O)OR⁶¹, and        —SCF₃;

L⁴ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-, or—C₂₋₃-alkynyl-;

R⁷ is an optionally mono- or polysubstituted group chosen fromC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, and heteroaryl,

-   -   wherein the substituents may be identical or different and are        chosen from halogen, —NO₂, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰,        —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl,        heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen,        —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCH₂F, —OCHF₂, —OCF₃, —NHOH,        —OC(═O)R⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰C(═O)R⁸¹, —NR⁸⁰C(═O)OR⁸¹,        —SiR⁸⁰R⁸¹R⁸² and —SCF₃;

R⁸ is chosen from H, halogen, CN, and C(═O)OH;

R¹⁰, R²⁰, R²¹, R³⁰, R⁴⁰, R⁴¹, R⁵⁰, R⁶⁰, R⁶¹, R⁷⁰, R⁸⁰, R⁸¹, and R⁸² ateach occurrence are independently chosen from H, C₁₋₆-alkyl,C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl, andheterocycloalkyl; and

n is 0, 1, or 2;

provided that when L¹ is —C(═O)— and R¹ is phenyl, R⁸ is not H or Br.

In certain embodiments, A is N, i.e., a compound of Formula I(a):

Preferably, when A is N, L¹ is —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or—C₁₋₆-alkyl-. More preferably, when A is N, L¹ is —C(═O)—C₀₋₃-alkyl-,—S(═O)₂—C₀₋₃-alkyl-, —C(═O)NR¹⁰—C₀₋₃-alkyl-, —S(═O)₂NR¹⁰—C₀₋₃-alkyl-,—C(═O)O—C₀₋₃-alkyl-, or —C₁₋₆-alkyl-. More preferably, when A is N, L¹is —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂—C₀₋₃-alkyl-, or—C₁₋₆-alkyl-. More preferably, when A is N, L¹ is —C(═O)—C₀₋₃-alkyl-,—S(═O)₂—C₀₋₃-alkyl-, or —C₁₋₆-alkyl-. More preferably, when A is N, L¹is —C(═O)—C₀₋₃-alkyl-, —S(═O)₂—, or —C₁₋₆-alkyl-. More preferably, whenA is N, L¹ is —C(═O), —C(═O)CH₂—, —S(═O)₂—, or —C₁₋₆-alkyl-. Morepreferably, when A is N, L¹ is —C(═O), —C(═O)CH₂—, —S(═O)₂—, —CH₂—, or—CH(CH₃). More preferably, when A is N, L¹ is —C(═O), —C(═O)CH₂—,—S(═O)₂—, or —CH₂—.

In certain embodiments, A is CH, i.e., a compound of Formula I(b):

Preferably, when A is CH, L¹ is —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O), —C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or—C₁₋₆-alkyl-. More preferably, when A is CH, L¹ is—C₁₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —S(═O)_(n)—C₀₋₃-alkyl-,—C₁₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-, —C₁₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or—C₁₋₆-alkyl-. More preferably, when A is CH, L¹ is—CH₂—C(═O)—C₀₋₃-alkyl-, —S(═O)_(n)—C₀₋₃-alkyl-,—CH₂—C(═O)NR¹⁰—C₀₋₃-alkyl-, —CH₂—C(═O)O—C₀₋₃-alkyl-,—CO₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or—C₁₋₆-alkyl-. More preferably, when A is CH, L¹ is—CH₂—C(═O)—C₀₋₃-alkyl-, —S(═O)_(n)—C₀₋₃-alkyl-,—CH₂—C(═O)NR¹⁰—C₀₋₃-alkyl-, —CH₂—C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or —CH₂—. Morepreferably, when A is CH, L¹ is —C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or —C₁₋₆-alkyl-. More preferably, when A isCH, L¹ is —NR¹⁰—C₀₋₃-alkyl-, —O—C₀₋₃-alkyl-, or —CH₂—. More preferably,when A is CH, L¹ is —NR¹⁰—, —O—C₀₋₃-alkyl-, or —CH₂—. More preferably,when A is CH, L¹ is —C₀₋₃-alkyl-O—C₀₋₃-alkyl- or —C₁₋₆-alkyl-. Morepreferably, when A is CH, L¹ is —C₀₋₃-alkyl-O—C₀₋₃-alkyl- or —CH₂—. Morepreferably, when A is CH, L¹ is —O—C₀₋₃-alkyl-, or —CH₂—. Morepreferably, when A is CH, L¹ is —O— or —CH₂—.

Preferably, when A is CH, L¹-R¹ is —C₁₋₃-alkyl-C(═O)—C₀₋₃-alkyl-R¹,—C₀₋₃-alkyl-S(═O), —C₀₋₃-alkyl-R¹, —C₁₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-, —C₁₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-OC(═O)NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-R¹,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-R¹, —C₁₋₆-alkyl-R¹, —C₂₋₆-alkenyl-R¹, or—C₂₋₆-alkynyl-R¹. More preferably, when A is CH, L¹-R¹ is—C₁₋₃-alkyl-C(═O)—C₀₋₃-alkyl-R¹, —C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-R¹,—C₁₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-, —C₁₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-OC(═O)NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-R¹,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-R¹, or —C₁₋₆-alkyl-R¹.

Preferably, R¹⁰ at each occurrence is independently chosen from H,C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably, R¹⁰ at each occurrenceis independently chosen from H and C₁₋₆-alkyl. More preferably, R¹⁰ ateach occurrence is H.

Preferably, L¹ is —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₆-alkyl-, —C₂₋₆-alkenyl-, or—C₂₋₆-alkynyl-.

Preferably, R¹ is an optionally mono- or polysubstituted group chosenfrom aryl and heteroaryl. More preferably, R¹ is an optionally mono- orpolysubstituted aryl group. More preferably, R¹ is an optionally mono-or polysubstituted group chosen from phenyl, pyridinyl, and furanyl.More preferably, R¹ is an optionally mono- or polysubstituted groupchosen from phenyl, pyridin-3-yl, and furan-2-yl.

Preferably, each R¹ substituent is independently chosen from halogen,—NO₂, —OR²⁰, —C(═O)OR²⁰, —NR²⁰R²¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, aryl,heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen,—S(═O)_(n)R²⁰, —S(═O)₂NR²⁰R²¹, —OCH₂F, —OCHF₂, —OCF₃, —NHOH, —OC(═O)R²⁰,—OC(═O)NR²⁰R²¹, —NR²⁰C(═O)R²¹, and —SCF₃. More preferably, each R¹substituent is independently chosen from halogen, —OR²⁰, —(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²⁰R²¹, —NR²⁰R²¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl,pseudohalogen, —S(═O)_(n)R²⁰, —S(═O)₂NR²⁰R²¹, —OCH₂F, —OCHF₂, —OCF₃,—NHOH, —OC(═O)R²⁰, —OC(═O)NR²⁰R²¹, —NR²⁰C(═O)R²¹, —NR²⁰C(═O)OR²¹, and—SCF₃. More preferably, each R¹ substituent is independently chosen fromhalogen, —OR²⁰, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²⁰R²¹, —NR²⁰R²¹,C₁₋₃-alkyl, C₁₋₃-haloalkyl, pseudohalogen, —OCF₃, —OC(═O)R²⁰,—OC(═O)NR²⁰R²¹, —NR²⁰C(═O)R²¹, —NR²⁰C(═O)OR²¹, and —SCF₃. Morepreferably, each R¹ substituent is independently chosen from halogen,—OR²⁰, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²⁰R²¹, —NR²⁰R²¹, C₁₋₃-alkyl,C₁₋₃-haloalkyl, pseudohalogen, —OCF₃, —NR²⁰C(═O)R²¹, and —NR²⁰C(═O)OR²¹.More preferably, each R¹ substituent is independently chosen fromhalogen, —OR²⁰, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²⁰R²¹, —NR²⁰R²¹,C₁₋₃-haloalkyl, —CN, and —OCF₃. More preferably, each R¹ substituent isindependently chosen from halogen, —C(═O)R²⁰, C₁₋₃-haloalkyl,pseudohalogen, and —OCF₃. More preferably, each R¹ substituent isindependently chosen from halogen, —C(═O)R²⁰, C₁₋₃-haloalkyl, —CN, and—OCF₃. More preferably, each R¹ substituent is independently chosen fromhalogen, —C(═O)—C₁₋₆-alkyl, C₁₋₃-haloalkyl, pseudohalogen, and —OCF₃.More preferably, each R¹ substituent is independently chosen fromhalogen, —C(═O)—C₁₋₆-alkyl, C₁₋₃-haloalkyl, —CN, and —OCF₃. Morepreferably, each R¹ substituent is independently chosen from chloro,fluoro, —CF₃, —C(═O)CH₃, —CN, and —OCF₃.

Preferably, R¹ is chosen from 2-chloro-3,6-difluorophenyl, phenyl,2,5-difluorophenyl, 2,4,5-trifluorophenyl,5-chloro-2-(trifluoromethyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl,2-chlorophenyl, 2,5-dichlorophenyl, 5-fluoro-2-(trifluoromethyl)phenyl,2,6-dichlorophenyl, 3-fluoro-2-(trifluoromethyl)phenyl, 3-chlorophenyl,3,5-dichlorophenyl, pyridin-3-yl, 2-acetyl-5-fluorophenyl,2-cyano-3,6-difluorophenyl, 5-(trifluoromethyl)furan-2-yl,2-(trifluoromethoxy)phenyl, and 2-chloropyridin-3-yl.

Preferably, R²⁰ and R²¹ at each occurrence are independently chosen fromH, C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably, R²⁰ and R²¹ at eachoccurrence are independently chosen from H and C₁₋₆-alkyl. Morepreferably, R²⁰ and R²¹ at each occurrence are H.

Preferably, R² and R³ are independently chosen from H and C₁₋₆-alkyl, orR² and R³ together form a carbonyl group. More preferably, R² and R³ areH, or R² and R³ together form a carbonyl group. More preferably, R² andR³ together form a carbonyl group. More preferably, R² and R³ are H.

Preferably, R² and R³ together form a carbonyl group, and R⁴ and R⁵ areindependently chosen from H and C₁₋₆-alkyl, or one of R⁴ and R⁵ forms adouble bond with R⁶.

Preferably, R⁴ and R⁵ are H, or one of R⁴ and R⁵ forms a double bondwith R⁶. More preferably, R⁴ and R⁵ are H.

Preferably, R⁶ is H, or R⁶ forms a double bond with R⁴ or R⁵. Morepreferably, R⁶ is H.

In certain embodiments, X is -L²G¹L³G²L⁴R⁷, i.e., a compound of FormulaI(c):

Preferably, L² is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—S(═O)_(n)—C₀₋₃-alkyl-, —C(═O)NR³⁰—C₀₋₃-alkyl-, —S(═O)₂NR³⁰—C₀₋₃-alkyl-,—C(═O)O—C₀₋₃-alkyl-, —CH₂—OC(═O)NR³¹—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR³¹—CH₂—, —CH₂—NR³⁰—C₀₋₃-alkyl-, —CH₂—O—C₀₋₃-alkyl-,—CH₂—OC(═O)—C₀₋₃alkyl-, —CH₂—NR¹⁰C(═O)—C₀₋₃-alkyl-,—CH₂—NR¹⁰S(═O)₂—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-, or—C₂₋₃-alkynyl-. More preferably, L² is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —S(═O)_(n)—C₀₋₃-alkyl-,—C(═O)NR³⁰—C₀₋₃-alkyl-, —S(═O)₂NR³⁰—C₀₋₃-alkyl-, —C(═O)O—C₀₋₃-alkyl-,—CH₂—OC(═O)NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR³⁰—CH₂—,—CH₂—NR³⁰—C₀₋₃-alkyl-, —CH₂—O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-,or —C₂₋₃-alkynyl-. More preferably, L² is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —S(═O)_(n)—C₀₋₃-alkyl-,—C(═O)NR³⁰—C₀₋₃-alkyl-, —S(═O)₂NR³⁰—C₀₋₃-alkyl-, —C(═O)O—C₀₋₃-alkyl-,—CH₂—OC(═O)NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR¹⁰—CH₂—,—CH₂—NR³⁰—C₀₋₃-alkyl-, —CH₂—O—C₀₋₃-alkyl-, or —C₂₋₃-alkynyl-. Morepreferably, L² is a bond, —C₀₋₃-alkyl-C(═O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or—C₂₋₃-alkynyl-. More preferably, L² is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C(═O)NR³⁰—C₀₋₃-alkyl-,—C(═O)O—C₀₋₃-alkyl-, or —C₂₋₃-alkynyl-. More preferably, L² is a bond,—C(═O)—C₀₋₃-alkyl-, —C(═O)NR³⁰—C₀₋₃-alkyl-, —C(═O)O—C₀₋₃-alkyl-, or—C₂₋₃-alkynyl-. More preferably, L² is a bond, —C(═O), —C(═O)O—,—C(═O)O—C₁₋₃-alkyl-, —C(═O)NR³⁰—C₀₋₃-alkyl-, or —C₂₋₃-alkynyl-. Morepreferably, L² is a bond, —C(═O)—, —C(═O)NR³⁰—, or —C₂₋₃-alkynyl-. Morepreferably, L² is a bond, —C(═O), —C(═O)O—, —C(═O)O—CH₂—,—C(═O)NH—(CH₂)₃—, —C(═O)NH—(CH₂)₂—, —C(═O)NH—CH₂—, —C(═O)NH—, —C≡C—, or—C≡C-CH₂—.

Preferably, R³⁰ at each occurrence is independently chosen from H,C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably R³⁰ at each occurrenceis independently chosen from H and C₁₋₆-alkyl. More preferably, R³⁰ ateach occurrence is H.

Preferably, G¹ is a bond, or an optionally mono- or polysubstitutedgroup chosen from aryl, heterocycloalkyl, and heteroaryl. Morepreferably, G¹ is a bond, or an optionally mono- or polysubstitutedgroup chosen from aryl and heteroaryl. More preferably, G¹ is a bond oran optionally mono- or polysubstituted aryl group. More preferably, G¹is a bond, or an optionally mono- or polysubstituted group chosen fromphenyl, pyridinyl, piperazinyl, pyrimidinyl, tetrahydropyridinyl,pyrazolyl, pyrrolyl, piperidinyl,4-carbonyl-1,3,8-triazaspiro[4.5]decanyl, pyrrolidinyl, and thiazolyl.

Preferably, each G¹ substituent is independently chosen from halogen,—NO₂, —OR⁴⁰, —C(═O)R⁴⁰, —C(═O)OR⁴⁰, —C(═O)NR⁴⁰R⁴¹, —NR⁴⁰R⁴¹, C₁₋₃-alkyl,C₁₋₃-haloalkyl, pseudohalogen, —S(═O)_(n)R⁴⁰, —S(═O)₂NR⁴⁰R⁴¹, —OCH₂F,—OCHF₂, —OCF₃, —NHOH, —OC(═O)R⁴⁰, —OC(═O)NR⁴⁰R⁴¹, —NR⁴⁰C(═O)R⁴¹,—NR⁴⁰C(═O)OR⁴¹, and —SCF₃. More preferably, each G¹ substituent isindependently chosen from halogen, —OR⁴⁰, —C(═O)R⁴⁰, —C(═O)OR⁴⁰,—C(═O)NR⁴⁰R⁴¹, —NR⁴⁰R⁴¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, —CN, —S(═O)OR⁴⁰,—S(═O)₂NR⁴⁰R⁴¹, —OCF₃, —OC(═O)R⁴⁰, —NR⁴⁰C(═O)R⁴¹, and —SCF₃. Morepreferably, each G¹ substituent is independently chosen from halogen,—OR⁴⁰, —C(═O)R⁴⁰, —C(═O)OR⁴⁰, —C(═O)NR⁴⁰R⁴¹, —NR⁴⁰R⁴¹, C₁₋₃-alkyl,C₁₋₃-haloalkyl, —CN, and —OCF₃. More preferably, each G¹ substituent isindependently chosen from halogen, —OR⁴⁰, C₁₋₃-alkyl, andC₁₋₃-haloalkyl. More preferably, each G¹ substituent is independentlychosen from halogen, —OR⁴⁰, and C₁₋₃-haloalkyl. More preferably, each G¹substituent is independently chosen from halogen and —OR⁴⁰. Morepreferably, each G¹ substituent is independently chosen from halogen andhydroxyl. More preferably, each G¹ substituent is independently chosenfrom chloro, fluoro, and hydroxyl. More preferably, G¹ is unsubstituted.

Preferably, R⁴⁰ and R⁴¹ at each occurrence are independently chosen fromH, C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably, R⁴⁰ and R⁴¹ at eachoccurrence are independently chosen from H and C₁₋₆-alkyl. Morepreferably, R⁴⁰ and R⁴¹ at each occurrence are H.

Preferably, L³ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O), —C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋3-alkyl-,—C₀₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-,—C₂₋₃-alkenyl-, or —C₂₋₃-alkynyl-. More preferably, L³ is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-. More preferably, L³ is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-. More preferably, L³ is abond, —C(═O)—C₀₋₃-alkyl-, —S(═O)₂—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—,—C(═O)O—C₀₋₃-alkyl-, —OC(═O)NR¹⁰—C₀₋₃-alkyl-, —NR⁵⁰—C₀₋₃-alkyl-,—O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-. More preferably, L³ is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-. More preferably, L³ is abond, —C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR⁵⁰—, —C(═O)O—C₀₋₃-alkyl-, —OC(═O)NR⁵⁰—C₀₋₃-alkyl-,—NR⁵⁰—C₀₋₃-alkyl-, —O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-. More preferably, L³is a bond, —C(═O)—, —C(═O)O—C₀₋₃-alkyl-, —C(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═)₂NR⁵⁰—, —O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —NR⁵⁰—C₀₋₃-alkyl-,—OC(═O)NR⁵⁰—C₀₋₃-alkyl-, or —C₁₋₁₃-alkyl-C(═O)NR⁵⁰—. More preferably, L³is a bond, —C(═O)—C₀₋₃-alkyl-, —S(═O)₂—, —C(═O)NR⁵⁰—, or —S(═O)₂NR¹⁰—.More preferably, L³ is a bond, —C(═O)—, —C(═O)O—C₀₋₃-alkyl-,—C(═O)N(C₁₋₃-alkyl)-C₀₋₃-alkyl-, —C(═O)NH—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NH—, —O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —NH—C₀₋₃-alkyl-,—OC(═O)NH—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-C(═O)NH—. More preferably, L³ is abond, —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, —C(═O)NH—(CH₂)₅—,—C(═O)NH—(CH₂)₃—, —C(═O)NH—(CH₂)₂—, —C(═O)NH—CH₂—, —C(═O)NH—,—C(═O)N(CH₃)—CH₂—, —C(═O)N(CH₃)—, —(CH₂)₂—S(═O)₂NH—, —CH₂—S(═O)₂NH—,—S(═O)₂NH—, —O—(CH₂)₂—, —O—CH₂—, —O—, —(CH₂)₂—, —CH₂—, —NH—(CH₂)₂—,—NH—CH₂—, —NH—, —OC(═O)NH—CH₂—, —OC(═O)NH—, or —CH₂—C(═O)NH—.

Preferably, R⁵⁰ at each occurrence is independently chosen from H,C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably, R⁵⁰ at each occurrenceis independently chosen from H and C₁₋₆-alkyl. More preferably, R⁵⁰ ateach occurrence is H.

Preferably, G² is a bond, or an optionally mono- or polysubstitutedgroup chosen from aryl, heterocycloalkyl, and heteroaryl. Morepreferably, G² is a bond, or an optionally mono- or polysubstitutedgroup chosen from aryl and heteroaryl. More preferably, G² is a bond, oran optionally mono- or polysubstituted group chosen from aryl andheterocycloalkyl. More preferably, G² is a bond or an optionally mono-or polysubstituted aryl group. More preferably, G² is a bond or anoptionally mono- or polysubstituted heterocycloalkyl group. Morepreferably, G² is a bond or an optionally mono- or polysubstitutedheteroaryl group. More preferably, G² is a bond, or an optionally mono-or polysubstituted group chosen from piperazinyl, pyrrolidinyl,piperidinyl, phenyl, 4-carbonyl-1,3,8-triazaspiro[4.5]decanyl, andthiazolyl.

Preferably, each G² substituent is independently chosen from halogen,—NO₂, —OR⁶⁰, —C(═O)R⁶⁰, —C(═O)OR⁶⁰, —C(═O)NR⁶⁰R⁶¹, —NR⁶⁰R⁶¹, C₁₋₃-alkyl,C₁₋₃-haloalkyl, pseudohalogen, —S(═O)_(n)R⁶⁰, —S(═O)₂NR⁶⁰R⁶¹, —OCH₂F,—OCHF₂, —OCF₃, —NHOH, —OC(═O)R⁶⁰, —OC(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)R⁶¹,—NR⁶⁰C(═O)OR⁶¹, and —SCF₃. More preferably, each G² substituent isindependently chosen from halogen, —OR⁶⁰, —C(═O)R⁶⁰, —C(═O)OR⁶⁰,—C(═O)NR⁶⁰R⁶¹, —NR⁶⁰R⁶¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, —CN, —S(═O)_(n)R⁶⁰,—S(═O)₂NR⁶⁰R⁶¹, —OCF₃, —OC(═O)R⁶⁰, —NR⁶⁰C(═O)R⁶¹, and —SCF₃. Morepreferably, each G² substituent is independently chosen from halogen,—OR⁶⁰, —C(═O)R⁶⁰, —C(═O)OR⁶⁰, —C(═O)NR⁶⁰R⁶¹, —NR⁶⁰R⁶¹, C₁₋₃-alkyl,C₁₋₃-haloalkyl, —CN, and —OCF₃. More preferably, each G² substituent isindependently chosen from halogen, —OR⁶⁰, C₁₋₃-alkyl, andC₁₋₃-haloalkyl. More preferably, each G² substituent is independentlychosen from halogen, —OR⁶⁰, and C₁₋₃-haloalkyl. More preferably, each G²substituent is independently chosen from halogen and —OR⁶⁰. Morepreferably, each G² substituent is independently chosen from halogen andhydroxyl. More preferably, each G² substituent is independently chosenfrom chloro, fluoro, and hydroxyl. More preferably, each G² substituentis hydroxyl. More preferably, G² is unsubstituted.

Preferably, R⁶⁰ and R⁶¹ at each occurrence are independently chosen fromH, C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably, R⁶⁰ and R⁶¹ at eachoccurrence are independently chosen from H and C₁₋₆-alkyl. Morepreferably, R⁶⁰ and R⁶¹ at each occurrence are H.

Preferably, L⁴ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-,—C₂₋₃-alkenyl-, or —C₂₋₃-alkynyl-. More preferably, L⁴ is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-. More preferably, L⁴ is abond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —S(═O)_(n)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-, —S(═O)₂NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —NR⁷⁰—C₀₋₃-alkyl-, —O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-. More preferably, L⁴ is a bond, —C(═O)—C₀₋₃-alkyl-,—S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁷⁰—, —S(═O)₂NR⁷⁰—,—C(═O)O—C₀₋₃-alkyl-, —NR¹⁰—C₀₋₃-alkyl-, —O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-.More preferably, L⁴ is a bond, —C(═O)—C₀₋₃-alkyl-, —S(═O)₂—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁷⁰—, —S(═O)₂NR⁷⁰—, —C(═O)O—C₀₋₃-alkyl-, —NR⁷⁰—, or—C₁₋₃-alkyl-. More preferably, L⁴ is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═)O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-. More preferably, L⁴ is abond, —C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁷⁰—, —C(═O)O—C₀₋₃-alkyl-,or —C₁₋₃-alkyl-. More preferably, L⁴ is a bond, —C(═O), —C₁₋₃-alkyl-,—C(═O)O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-C(═O)NH—. More preferably, L⁴ is abond, —C(═O)—, —(CH₂)₂—, —CH₂—, —C(═O)O—, —C(═O)O—CH₂—, or —CH₂—C(═O)NH.

Preferably, R⁷⁰ at each occurrence is independently chosen from H,C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably, R⁷⁰ at each occurrenceis independently chosen from H and C₁₋₆-alkyl. More preferably, R⁷⁰ ateach occurrence is H.

Preferably, R⁷⁰ is an optionally mono- or polysubstituted group chosenfrom C₁₋₆-alkyl, aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, andheteroaryl. More preferably, R⁷ is an optionally mono- orpolysubstituted group chosen from C₁₋₆-alkyl, aryl, heterocycloalkyl,and heteroaryl. More preferably, R⁷ is an optionally mono- orpolysubstituted group chosen from aryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, and heteroaryl. More preferably, R⁷ is an optionallymono- or polysubstituted group chosen from aryl, heterocycloalkyl, andheteroaryl. More preferably, R⁷ is an optionally mono- orpolysubstituted group chosen from pyridinyl, phenyl, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, isopentyl,hexyl, piperazinyl, pyrrolidinyl, morpholinyl, pyrimidinyl,dihydropyridinyl, tetrahydropyridinyl, propynyl, pyrazolyl, pyrrolyl,piperidinyl, 1,3-dihydro-2-carbonylbenzoimidazolyl,4-carbonyl-1,3,8-triazaspiro[4.5]decanyl, thieno[3,2-d]pyrimidinyl,furo[3,2-c]pyridinyl, benzo[d]isoxazolyl, thienyl, quinolinyl,pyrazinyl, thiazolyl, naphthalenyl, indanyl, cyclohexyl,tetrahydrofuranyl, indolyl, and isoindolyl. More preferably, R⁷ is anoptionally mono- or polysubstituted group chosen from pyridin-3-yl,piperazin-1-yl, phenyl, pyrrolidin-1-yl, morpholin-4-yl, methyl, ethyl,propyl, butyl, pentyl, hexyl, piperidin-1-yl, pyridin-4-yl,isoxazol-4-yl, pyrimidin-5-yl, propyn-1-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, pyrazol-4-yl, pyrrol-3-yl,pyrimidin-2-yl, isopropyl, isobutyl, isopentyl, tert-butyl,1,3-dihydro-2-carbonylbenzoimidazol-1-yl,4-carbonyl-1,3,8-triazaspiro[4.5]decan-8-yl,thieno[3,2-d]pyrimidin-4-yl, furo[3,2-c]pyridin-4-yl,benzo[d]isoxazol-3-yl, pyridin-2-yl, piperidin-4-yl, thien-2-yl,quinolin-4-yl, pyrazin-2-yl, thiazol-4-yl, naphthalen-1-yl, indan-1-yl,cyclohexyl, 4-biphenyl, tetrahydrofuran-2-yl, indan-2-yl, thiazol-2-yl,indol-3-yl, and isoindol-2-yl.

Preferably, at least one of G¹ and R⁷ is an optionally mono- orpolysubstituted group chosen from aryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, and heteroaryl.

Preferably, each R⁷ substituent is independently chosen from halogen,—OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl,C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl,pseudohalogen, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCH₂F, —OCHF₂, —OCF₃,—NHOH, —OC(═O)R⁸⁰, —OC(═O)NR⁸⁰R⁸¹, —NR⁸⁰C(═O)R⁸¹, —NR⁸⁰C(═O)OR⁸¹,—SiR⁸⁰R⁸¹R⁸² and —SCF₃. More preferably, each R⁷ substituent isindependently chosen from halogen, OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰,—C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen, —S(═O)_(n)R⁸⁰,—S(═O)₂NR⁸⁰R⁸¹, —OCF₃, —OC(═O)R⁸⁰, —NR⁸⁰C(═O)R⁸¹, —SiR⁸⁰R⁸¹R⁸² and—SCF₃. More preferably, each R⁷ substituent is independently chosen fromhalogen, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹,C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, pseudohalogen, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCF₃,—OC(═O)R⁸⁰, and —NR⁸⁰C(═O)R⁸¹. More preferably, each R⁷ substituent isindependently chosen from halogen, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰,—C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen, —S(═O)_(n)R⁸⁰,—S(═O)₂NR⁸⁰R⁸¹, —OCF₃, and —SiR⁸⁰R⁸¹R⁸². More preferably, each R⁷substituent is independently chosen from halogen, —OR⁸⁰, —C(═O)R⁸⁰,—C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl,heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, cyano, —S(═O)₂R⁸⁰,—S(═O)₂NR⁸⁰R⁸¹, —OCF₃, and —SiR⁸⁰R⁸¹R⁸². More preferably, each R⁷substituent is independently chosen from methyl, carboxy,N,N-dimethylamino, acetyl, methanesulfonyl, aminocarbonyl,ethylaminocarbonyl, cyano, ethoxycarbonyl, methoxycarbonyl,pyrrolidin-1-yl, chloro, morpholin-4-yl, fluoro, methoxy,tert-butoxycarbonyl, pyrrolidin-1-yl, tert-butoxycarbonylamino, amino,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, isopentyl, triisopropylsilyl, phenyl,pyrimidin-2-yl, 1,3-dihydro-2-carbonylbenzoimidazol-1-yl,trifluoromethyl, thieno[3,2-d]pyrimidin-4-yl, furo[3,2-c]pyridin-4-yl,fluoro, pyridin-2-yl, trifluoromethoxy, thien-2-yl, pyridin-4-yl,pyridin-3-yl, pyrrolidin-1-yl, sulfamoyl, pyrazin-2-yl, naphthalen-1-yl,phenoxy, tetrahydrofuran-2-ylcarbonyl, tetrahydrofuran-2-yl,indan-2-ylaminocarbonyl, cyclohexyl, pyridin-3-yl, thiazol-2-yl,acetamindo, indol-3-yl, benzoyl, isopropylaminocarbonyl,morpholin-4-ylcarbonyl, cyclohexylaminocarbonyl,indan-1-ylaminocarbonyl, indan-2-ylaminocarbonyl, andisoindol-2-ylcarbonyl.

Preferably, R⁸⁰, R⁸¹, and R⁸² at each occurrence are independentlychosen from H, C₁₋₆-alkyl, and C₁₋₆-haloalkyl. More preferably, R⁸⁰,R⁸¹, and R⁸² at each occurrence are independently chosen from H andC₁₋₆-alkyl. More preferably, R⁸⁰, R⁸¹, and R⁸² at each occurrence are H.

Preferably, R⁸⁰ at each occurrence is independently chosen from H,C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl, and heterocycloalkyl. Morepreferably, R⁸⁰ at each occurrence is independently chosen from H,C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, and heteroaryl. More preferably, R⁸⁰at each occurrence is independently chosen from H, C₁₋₆-alkyl,C₁₋₆-haloalkyl, and aryl.

Preferably, when R⁷ is C₁₋₆-alkyl, at least one of L², G¹, L³, G², or L⁴is not a bond.

Preferably, R⁷ is chosen from pyridin-3-yl, 4-methylpiperazin-1-yl,4-carboxyphenyl, pyrrolidin-1-yl, morpholin-4-yl,N,N-dimethylaminomethyl, N,N-dimethylaminoethyl,N,N-dimethylaminopropyl, N,N-dimethylaminobutyl,N,N-dimethylaminopentyl, N,N-dimethylaminohexyl, 4-acetylphenyl, methyl,ethyl, 4-methanesulfonylphenyl, benzamidyl, N-ethylbenzamidyl,2-cyanopyridin-5-yl, 2-ethoxycarbonylpyridin-5-yl,4-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 3-carboxyphenyl,3-methoxycarbonylphenyl, 4-(1-pyrrolidinyl)piperidin-1-yl,2-carboxypyridin-5-yl, 3-ethoxycarbonylpyridin-5-yl,3-carboxypyridin-5-yl, 3-chloro-2-morpholin-4-ylpyridin-4-yl,3-fluoro-2-morpholin-4-ylpyridin-4-yl, 3,5-dimethylisoxazol-4-yl,2-(4-morpholinyl)pyrimidin-5-yl, 2-methoxypyrimidin-5-yl,1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl,1,2,3,6-tetrahydropyridin-4-yl, 2-chloropyridin-5-yl,2-(1-pyrrolidinyl)pyridin-5-yl, 2-chloropyridin-4-yl,3-tert-butoxycarbonylaminopropyn-1-yl, 3-aminopropyn-1-yl,3-dimethylaminopropyn-1-yl,3-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)propyn-1-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, 2-aminopyridin-5-yl,2-(1-pyrrolidinyl)pyridin-4-yl, 2-(4-morpholinyl)pyridin-4-yl,3-(4-morpholinyl)phenyl, 1-isopentylpyrazol-4-yl,2-(1-piperazinyl)pyridin-4-yl, 4-acetylpiperazin-1-yl, pyrazol-4-yl,pyrrol-3-yl, 1-(triisopropylsilyl)pyrrol-3-yl, 1-methylpyrazol-4-yl,piperidin-1-yl, 4-methoxypiperidin-1-yl, 4-phenylpiperazin-1-yl,pyrimidin-2-yl, phenyl, methyl, ethyl, isopropyl, isobutyl, isopentyl,tert-butyl, piperazin-1-yl, 4-(2-pyrimidinyl)piperazin-1-yl,4-chlorophenyl, 1,3-dihydro-2-carbonylbenzoimidazol-1-yl,4-(1,3-dihydro-2-carbonylbenzoimidazol-1-yl)piperidin-1-yl,2-methoxyphenyl, 3-(trifluoromethyl)phenyl, 4-phenylpiperidin-1-yl,3,4-dichlorophenyl, benzhydryl, benzyl,4-carbonyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl,4-carbonyl-1,3,8-triazaspiro[4.5]decan-8-yl,thieno[3,2-d]pyrimidin-4-yl,4-thieno[3,2-d]pyrimidin-4-ylpiperazin-1-yl, 4-methoxyphenyl,furo[3,2-c]pyridin-4-yl, 4-furo[3,2-c]pyridin-4-ylpiperazin-1-yl,6-fluorobenzo[d]isoxazol-3-yl, 3-chlorophenyl, pyridin-2-yl,2-pyridinylmethyl, 2-(2-pyridinyl)ethyl, 1-ethoxycarbonylpiperidin-4-yl,4-(trifluoromethoxy)phenyl, 4-(4-morpholinyl)piperidin-1-yl, thien-2-yl,2-thienylmethyl, 2-(2-thienyl)ethyl, pyridin-4-yl, 4-pyridinylmethyl,3-pyridinylmethyl, quinolin-4-yl, 2-methylquinolin-4-yl,1-pyrrolidinylmethyl, 3,5-bis(trifluoromethyl)phenyl, 4-sulfamoylphenyl,pyrazin-2-yl, 4-(2-pyrazinyl)piperazin-1-yl, thiazol-4-yl,2-phenylthiazol-4-yl, naphthalene-1-yl, 1-naphthalenylmethyl,indan-1-yl, cyclohexyl, 4-biphenyl, 2-phenoxyethyl, phenoxymethyl,tetrahydrofuran-2-yl, 4-(2-tetrahydrofuranylcarbonyl)piperazin-1-yl,phenethyl, 2-tetrahydrofuranylmethyl, 2-chlorophenyl,2-(trifluoromethyl)phenyl, indan-2-yl, 3-(2-indanylaminocarbonyl)phenyl,cyclohexylmethyl, 2-(3-pyridinyl)pyrrolidin-1-yl,4-(4-morpholinyl)phenyl, thiazol-2-yl, 4-(2-thiazolyl)piperazin-1-yl,2-(4-morpholinyl)pyridin-5-yl, 4-acetamidophenyl, indol-3-yl,4-(3-indolyl)piperidin-1-yl, 4-benzoylpiperazin-1-yl,1-methylpiperidin-4-yl, isopropylaminocarbonylmethyl,3-(4-morpholinylcarbonyl)phenyl, 3-methoxyphenyl,3-(cyclohexylaminocarbonyl)phenyl, 4-(trifluoromethyl)phenyl,methoxymethyl, methoxyethyl, 4-(4-morpholinylcarbonyl)phenyl,4-(1-indanylaminocarbonyl)phenyl, 4-(2-indanylaminocarbonylphenyl,isoindol-2-yl, and 4-(2-isoindolylcarbonyl)phenyl.

In certain embodiments, X is R⁸, i.e., a compound of Formula I(d):

Preferably, R⁸ is H, Br, I, CN, or C(═O)OH. More preferably, R⁸ is Br,I, CN, or C(═O)OH. More preferably, R⁸ is I, CN, or C(═O)OH. Morepreferably, R⁸ is I.

In addition to having ALK and c-Met inhibitory activity, the compoundsof Formula I(d) are useful as intermediates for the preparation of othercompounds of Formula I (e.g., compounds of Formula I(c)).

Preferably, n is 0 or 2. More preferably, n is 0. More preferably, n is2.

The present invention provides a compound of Formula I in which A, L¹,R¹, R², R³, R⁴, R⁵, R⁶, L², G¹, L³, G², L⁴, R⁷, R⁸, R¹⁰, R²⁰, R²¹, R³⁰,R⁴⁰, R⁴¹, R⁵⁰, R⁶⁰, R⁶¹, R⁷⁰, R⁸⁰, R⁸¹, R⁸², and n are independentlychosen as set forth in any of the above-recited definitions. Thus, thepresent invention includes a compound of Formula I having A, L¹, R¹, R²,R³, R⁴, R⁵, R⁶, L², G¹, L³, G², L⁴, R⁷, R⁸, R¹⁰, R²⁰, R²¹, R³⁰, R⁴⁰,R⁴¹, R⁵⁰, R⁶⁰, R⁶¹, R⁷⁰, R⁸⁰, R⁸¹, R⁸², and n defined by any combinationof the broader and narrower definitions of these substituents as setforth above. For example, included within the scope of the presentinvention are compounds of Formula I in which R¹⁰, R²⁰, R²¹, R³⁰, R⁴⁰,R⁴¹, R⁵⁰, R⁵¹, R⁶⁰, R⁶¹, R⁷⁰, R⁸⁰, R⁸¹, and R⁸² at each occurrence areindependently chosen from H and C₁₋₆-alkyl. As another example, alsoincluded within the scope of the present invention are compounds ofFormula I in which R¹⁰, R²⁰, R²¹, R³⁰, R⁴⁰, R⁴¹, R⁵⁰, R⁵¹, R⁶⁰, R⁶¹,R⁷⁰, R⁸⁰, R⁸¹, and R⁸² at each occurrence are H. As another example,also included within the scope of the present invention are compounds ofFormula I in which G¹ is a bond, or an optionally mono- orpolysubstituted group chosen from aryl, heterocycloalkyl, andheteroaryl, and each G¹ substituent is independently chosen from halogenand —OR⁴⁰. As another example, also included within the scope of thepresent invention are compounds of Formula I in which G² is a bond, oran optionally mono- or polysubstituted group chosen from aryl,heterocycloalkyl, and heteroaryl, and each G² substituent isindependently chosen from halogen and —OR⁶⁰. As another example, alsoincluded within the scope of the present invention are compounds ofFormula I in which R⁷ is an optionally mono- or polysubstituted groupchosen from C₁₋₆-alkyl, aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, andheteroaryl, and each R⁷ substituent is independently chosen fromhalogen, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹,C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, cyano, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCF₃, and—SiR⁸⁰R⁸¹R⁸². As another example, also included within the scope of thepresent invention are compounds of Formula I in which at least one of G¹and R⁷ is an optionally mono- or polysubstituted group chosen from aryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl, each G¹ substituentis independently chosen from halogen and —OR⁴⁰, and each R⁷ substituentis independently chosen from halogen, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰,—C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, cyano, —S(═O)_(n)R⁸⁰,—S(═O)₂NR⁸⁰R⁸¹, —OCF₃, and —SiR⁸⁰R⁸¹R⁸². As another example, alsoincluded within the scope of the present invention are compounds ofFormula I in which

A is N;

L¹ is —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O), —C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or —C₁₋₆-alkyl-;

R¹ is an optionally mono- or polysubstituted group chosen from aryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl, wherein thesubstituents may be the same or different and are chosen from halogen,—OR²⁰, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²⁰R²¹, —NR²⁰R²¹, C₁₋₃-haloalkyl,—CN, and —OCF₃;

R² and R³ are independently chosen from H, OH, and C₁₋₆-alkyl, or R² andR³ together form a carbonyl group;

R⁴ and R⁵ are independently chosen from H and C₁₋₆-alkyl, or R⁴ and R⁵together form a carbonyl group, or one of R⁴ and R⁵ forms a double bondwith R⁶;

R⁶ is chosen from H and C₁₋₆-alkyl, or R⁶ forms a double bond with R⁴ orR⁵;

X is -L²G¹L³G²L⁴R⁷;

L² is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —S(═O)_(n)—C₀₋₃-alkyl-,—C(═O)NR³⁰—C₀₋₃-alkyl-, —S(═O)₂NR³⁰—C₀₋₃-alkyl-, —C(═O)O—C₀₋₃-alkyl-,—CH₂—OC(═O)NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR³⁰—CH₂—,—CH₂—NR³⁰—C₀₋₃-alkyl-, —CH₂—O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-,or —C₂₋₃-alkynyl-;

G¹ is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl, whereinthe substituents may be identical or different and are chosen fromhalogen, —OR⁴⁰, and C₁₋₃-haloalkyl;

L³ is a bond, —C(═O)—C₀₋₃-alkyl-, —S(═O)₂—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—,—C(═O)O—C₀₋₃-alkyl-, —OC(═O)NR⁵⁰—C₀₋₃-alkyl-, —NR⁵⁰—C₀₋₃-alkyl-,—O—C₀₋₃-alkyl-, or —C₁₋₃-alkyl-;

G² is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl, whereinthe substituents may be identical or different and are chosen fromhalogen, —OR⁶⁰, and C₁₋₃-haloalkyl;

L⁴ is a bond, —C(═O)—C₀₋₃-alkyl-, —S(═O)₂—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁷⁰—, —S(═O)₂NR¹⁰—, —C(═O)O—C₀₋₃-alkyl-, —NR⁷⁰—, or—C₁₋₃-alkyl-;

R⁷ is an optionally mono- or polysubstituted group chosen fromC₁₋₆-alkyl, aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl,wherein the substituents may be identical or different and are chosenfrom halogen, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹,C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, pseudohalogen, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCF₃,—OC(═O)R⁸⁰, and —NR⁸⁰C(═O)R⁸¹;

R¹⁰, R²⁰, R²¹, R³⁰, R⁴⁰, R⁵⁰, R⁶⁰, R⁷⁰, and R⁸¹ at each occurrence areindependently chosen from H, C₁₋₆-alkyl, and C₁₋₆-haloalkyl;

R⁸⁰ at each occurrence is independently chosen from H, C₁₋₆-alkyl, andC₁₋₆-haloalkyl, aryl, and heteroaryl; and

n is 0 or 2. As another example, also included within the scope of thepresent invention are compounds of Formula I in which

A is N;

L¹ is —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂—C₀₋₃-alkyl-, or—C₁₋₆-alkyl-;

R¹ is an optionally mono- or polysubstituted group chosen from aryl andheteroaryl, wherein the substituents may be identical or different andare chosen from halogen, —C(═O)R²⁰, C₁₋₃-haloalkyl, —CN, and —OCF₃;

R² and R³ are independently chosen from H and C₁₋₆-alkyl, or R² and R³together form a carbonyl group;

R⁴ and R⁵ are H, or one of R⁴ and R⁵ forms a double bond with R⁶;

R⁶ is H, or R⁶ forms a double bond with R⁴ or R⁵;

X is -L²G¹L³G²L⁴R⁷;

L² is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or—C₂₋₃-alkynyl-;

G¹ is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, heterocycloalkyl, and heteroaryl, wherein the substituentsmay be identical or different and are chosen from halogen and —OR⁴⁰;

L³ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-;

G² is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, heterocycloalkyl, and heteroaryl, wherein the substituentsmay be identical or different and are chosen from halogen and —OR⁶⁰.

L⁴ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-;

R⁷ is an optionally mono- or polysubstituted group chosen fromC₁₋₆-alkyl, aryl, heterocycloalkyl, and heteroaryl, wherein thesubstituents may be identical or different and are chosen from halogen,—OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl,C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl,pseudohalogen, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCF₃, and —SiR⁸⁰R⁸¹R⁸²;

R²⁰, R³⁰, R⁴⁰, R⁵⁰, R⁶⁰, R⁷⁰, R⁸⁰, R⁸¹, and R⁸² at each occurrence areindependently chosen from H, C₁₋₆-alkyl, and C₁₋₆-haloalkyl; and

n is 2. As another example, also included within the scope of thepresent invention are compounds of Formula I in which

A is CH;

L¹ is —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or —C₁₋₆-alkyl-;

R¹ is an optionally mono- or polysubstituted group chosen from aryl andheteroaryl, wherein the substituents may be identical or different andare chosen from halogen, —C(═O)R²⁰, C₁₋₃-haloalkyl, —CN, and —OCF₃;

R² and R³ are independently chosen from H and C₁₋₆-alkyl, or R² and R³together form a carbonyl group;

R⁴ and R⁵ are H, or one of R⁴ and R⁵ forms a double bond with R⁶;

R⁶ is H, or R⁶ forms a double bond with R⁴ or R⁵;

X is -L²G¹L³G²L⁴R⁷;

L² is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or—C₂₋₃-alkynyl-;

G¹ is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, heterocycloalkyl, and heteroaryl, wherein the substituentsmay be identical or different and are chosen from halogen and —OR⁴⁰;

L³ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-;

G² is a bond, or an optionally mono- or polysubstituted group chosenfrom aryl, heterocycloalkyl, and heteroaryl, wherein the substituentsmay be identical or different and are chosen from halogen and —OR⁶⁰.

L⁴ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-;

R⁷ is an optionally mono- or polysubstituted group chosen fromC₁₋₆-alkyl, aryl, heterocycloalkyl, and heteroaryl, wherein thesubstituents may be identical or different and are chosen from halogen,—OR⁸⁰, —C(═O)R¹⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkylC₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl,pseudohalogen, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCF₃, and —SiR⁸⁰R⁸¹R⁸²;

R²⁰, R³⁰, R⁴⁰, R⁵⁰, R⁶⁰, R⁷⁰, R⁸⁰, R⁸¹, and R⁸² at each occurrence areindependently chosen from H, C₁₋₆-alkyl, and C₁₋₆-haloalkyl; and

n is 2.

In one embodiment, the present invention provides a compound of FormulaI(c) chosen from:

-   1-(2-Chloro-3,6-difluorobenzyl)-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   4-[1-(2-Chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid ethyl ester;-   4-[1-(2-Chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid;-   1-(2-Chloro-3,6-difluorobenzyl)-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic    acid ethyl ester;-   4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic    acid;-   1-Benzyl-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)benzamide;-   S-1-Benzyl-7-[4-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-morpholin-4-yl-propyl)benzamide;-   4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(4-dimethylaminobutyl)benzamide;-   4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(6-dimethylaminohexyl)benzamide;-   1-Benzyl-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-1H-pyrido[2,3-b]pyrazin-2-one;-   S-1-Benzyl-7-[3-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino-ethyl)benzamide;-   1-Benzyl-7-[3-(pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   7-(4-Acetylphenyl)-1-benzyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide;-   4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzamide;-   1-Benzyl-7-(4-methanesulfonyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-Benzyl-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-Benzyl-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide;-   5-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile;-   5-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carboxylic    acid ethyl ester;-   3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic    acid methyl ester;-   3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic    acid;-   1-Benzyl-7-pyridin-3-yl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid    ethyl ester;-   4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic    acid;-   [4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-methylpiperazin-1-yl)methanone;-   [4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-((S)-2-pyrrolidinylmethylpyrrolidin-1-yl)methanone;-   [4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;-   Phenyl-(7-pyridin-3-yl-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone;-   4-(1-Benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic    acid ethyl ester;-   2-Pyrrolidin-1-yl-ethanesulfonic    acid[4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide;-   2-Pyrrolidin-1-yl-ethanesulfonic    acid[4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide;-   2-(4-Methylpiperazin-1-yl)-ethanesulfonic    acid[4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide;-   2-Pyrrolidin-1-yl-ethanesulfonic    acid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;-   2-[Ethyl-((S)-1-pyrrolidin-1-ylmethyl-propyl)-amino]-ethanesulfonic    acid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;-   2-Morpholin-4-yl-ethanesulfonic    acid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;-   2-Pyrrolidin-1-yl-ethanesulfonic    acid{4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;-   4-(1-Benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino-ethyl)benzamide;-   4-(1-Benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-dimethylamino-propyl)benzamide;-   {7-[4-(4-Methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}phenylmethanone;-   4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid ethyl ester;-   4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid;-   1-(2,5-Difluorobenzyl)-7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin-1-yl-ethyl)benzamide;-   1-(2,5-Difluorobenzyl)-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-(2,5-Difluorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   (S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylic    acid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;-   4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid ethyl ester;-   4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid;-   {4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone;-   {4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;-   {4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;-   {4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-morpholin-4-yl-methanone;-   1-(2,5-Difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carbonitrile;-   5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carboxylic    acid;-   5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic    acid ethyl ester;-   5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic    acid;-   1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid ethyl ester;-   {5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2-yl}morpholin-4-yl-methanone;-   [1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-methylpiperazin-1-yl)methanone;-   1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid[2(4-methylpiperazin-1-yl)ethyl]amide;-   7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   ((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-{4-[1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone;-   7-[4-(4-Methylpiperazine-1-carbonyl)phenyl]-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   (4-Methylpiperazin-1-yl)-{4-[1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone;-   (2,5-Difluorophenyl)-{7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-methanone;-   (2,5-Difluorophenyl)-{7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-methanone;-   1-(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   {4-[1-(2,5-Difluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone;-   {4-[1-(2,5-Difluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;-   {4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;-   {4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(3-chloro-2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(3-fluoro-2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(3,5-dimethyl-isoxazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   {4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)-pyrimidin-5-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyrimidin-5-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   7-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   2-Phenyl-1-{7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-ethanone;-   2-(2,5-Difluorophenyl)-1-{7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}ethanone;-   2-(2,5-Difluorophenyl)-1-{7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}ethanone;-   {4-[1-(5-Chloro-2-trifluoromethylbenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;-   1-(5-Chloro-2-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-5-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Difluorobenzenesulfonyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-Benzenesulfonyl-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chlorobenzenesulfonyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Dichlorobenzyl)-7-(2-methoxypyrimidin-5-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic    acid tert-butyl ester;-   1-(2,5-Dichlorobenzyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   {4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;-   1-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid ethyl ester;-   4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid;-   S-1-(2,6-Dichlorobenzyl)-7-[4-((2-pyrrolidin-1-yl)methylpyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin-1-yl-ethyl)benzamide;-   4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(6-dimethylaminohexyl)benzamide;-   4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(4-dimethylaminobutyl)benzamide;-   7-[4-(4-Methylpiperazine-1-carbonyl)phenyl]-1-[1-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   S-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}-(4-{1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (4-Methylpiperazin-1-yl)-(4-{1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   S-(4-{1-[1-(2,5-Difluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;-   1-[1-(2,5-Difluorophenyl)ethyl]-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   S-(4-{1-[1-(2,5-Difluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;-   1-(2,5-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   S-1-(2,5-Dichlorobenzyl)-7-[4-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   S-{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;-   {4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;-   1-(2,6-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   {4-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;-   {4-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;-   7-(6-Chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Dichlorobenzyl)-7-(6-pyrrolidin-1-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   7-(2-Chloropyridin-4-yl)-1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   {3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamic    acid tert-butyl ester;-   3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine;-   {3-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamic    acid tert-butyl ester;-   3-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine;-   N-{3-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}-2-dimethylamino-acetamide;-   {3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}-dimethylamine;-   1-(2,5-Dichlorobenzyl)-7-[3-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)prop-1-ynyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Dichlorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(2-pyrrolidin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   5-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2-ylamine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Dichlorobenzyl)-4-methyl-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-[1-(3-methylbutyl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic    acid ethyl ester;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic    acid ethyl ester;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic    acid;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic    acid;-   (2-{4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyrazol-1-yl}ethyl)dimethylamine;-   1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine;-   1-[4-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}pyridin-2-yl)piperazin-1-yl]ethanone;-   1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine;-   1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine;-   1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   {1-[(5-Chloro-2-trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}piperidin-1-yl-methanone;-   {1-[(5-Chloro-2-trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-(4-methoxy-piperidin-1-yl)methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperazin-1-yl)-methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-pyrimidin-2-yl-piperazin-1-yl)-methanone;-   [4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   1-{1-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperidin-4-yl)}-1,3-dihydrobenzoimidazol-2-one;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-methoxyphenyl)piperazin-1-yl]methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperidin-1-yl)methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(3,4-dichlorophenyl)-piperazin-1-yl]methanone;-   (4-Benzhydrylpiperazin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   (4-Benzylpiperidin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   8-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4-methoxybenzyl)piperazin-1-yl]methanone;-   (4-Benzoylpiperazin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]methanone;-   [4-(3-Chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (2-pyridin-2-yl-ethyl)amide;-   4-{[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]amino}piperidine-1-carboxylic    acid ethyl ester;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (1-benzyl-piperidin-4-yl)amide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (2,2-diphenylethyl)amide;-   1-{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin-1-yl}ethanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid 3-chlorobenzylamide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid 4-(trifluoromethoxy)benzylamide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-morpholin-4-yl-piperidin-1-yl)methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (2-thiophen-2-yl-ethyl)amide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid benzhydrylamide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (pyridin-4-ylmethyl)amide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (pyridin-3-ylmethyl)amide;-   2-{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin-1-yl}-N-isopropylacetamide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid 3,5-bis-(trifluoromethyl)benzylamide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid[2-(4-sulfamoylphenyl)ethyl]amide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (2-phenylthiazol-4-yl-methyl)amide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]morpholin-4-yl-methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (naphthalen-1-yl-methyl)amide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid indan-1-ylamide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid benzylamide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4-methoxyphenyl)piperazin-1-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid cyclohexylamide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (biphenyl-4-ylmethyl)amide;-   [4-(4-Chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (2-phenoxyethyl)amide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid phenethyl-amide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid (tetrahydrofuran-2-yl-methyl)amide;-   [4-(4-Chlorobenzyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid 2-chloro-benzylamide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-(trifluoromethyl)phenyl)piperazin-1-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid 4-methoxybenzylamide;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid indan-2-ylamide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenethyl-piperazin-1-yl)methanone;-   [4-(2-Chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   [(4-Cyclohexylmethyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid 4-sulfamoyl-benzylamide;-   [1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2-pyridin-3-yl-pyrrolidin-1-yl)methanone;-   {4-[5-(2,5-Dichlorophenoxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]phenyl}-4-methyl-piperazin-1-yl)methanone;-   4-(2-Chloro-3,6-difluorophenoxy)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   {4-[5-(3-Chlorophenoxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]-phenyl}-(4-methylpiperazin-1-yl)methanone;-   {4-[5-(3,5-Dichlorophenoxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;-   (4-Methylpiperazin-1-yl)-{4-[5-(pyridine-3-yloxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]phenyl}methanone;-   1-(4-Fluoro-2-{6-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-yloxy}phenyl)ethanone;-   4-(3-Chlorophenoxy)-6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   4-(3-Chlorophenoxy)-6-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   4-(3-Chlorophenoxy)-6-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   4-(3-Chlorophenoxy)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   4-(2,5-Difluorobenzyl)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-morpholin-4-yl-piperidin-1-yl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thiazol-2-yl-piperazin-1-yl)methanone;-   3,6-Difluoro-2-[7-(6-morpholin-4-yl-pyridin-3-yl)-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-ylmethyl]benzonitrile;-   7-(6-Morpholin-4-yl-pyridin-3-yl)-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   7-[2-(4-Methylpiperazin-1-yl)pyridin-4-yl]-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid[4-(dimethylamino)butyl]amide;-   4-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic    acid ethyl ester;-   4-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic    acid;-   4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid ethyl ester;-   4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic    acid;-   {4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)methanone;-   N-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)acetamide;-   (4-Pyrrolidin-1-yl-piperidin-1-yl)-(4-{1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperazin-1-yl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin-1-yl)methanone;-   [4-(4-Chlorophenyl)-piperazin-1-yl]-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   [4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   1-[1-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-1,3-dihydrobenzoimidazol-2-one;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin-1-yl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(1H-indol-3-yl)piperidin-1-yl]methanone;-   (4-Benzhydrylpiperazin-1-yl)-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (4-Benzylpiperidin-1-yl)-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-1-yl]methanone;-   8-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-ylpiperazin-1-yl)methanone;-   [4-(4-Chlorobenzyl)piperazin-1-yl]-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-1-yl]methanone;-   (4-Benzoylpiperazin-1-yl)-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-furo[3,2-c]pyridin-4-ylpiperazin-1-yl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]methanone;-   4-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoylamino)piperidine-1-carboxylic    acid ethyl ester;-   N-(1-Benzylpiperidin-4-yl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(1-methylpiperidin-4-yl)benzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzamide;-   N-[3,5-Bis(trifluoromethyl)benzyl]-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   N-Benzhydryl-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-4-ylmethylbenzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-3-ylmethylbenzamide;-   2-[4-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]-N-isopropylacetamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)morpholin-4-ylmethanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-naphthalen-1-ylmethylbenzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-1-ylbenzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3-methoxyphenyl)piperazin-1-yl]methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-cyclohexylbenzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methanesulfonylbenzyl)benzamide;-   N-(2-Chlorobenzyl)-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   N-(4-Chlorobenzyl)-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   N-(3-Chlorobenzyl)-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(3-methoxybenzyl)benzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzamide;-   N-Benzyl-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   [4-(3-Chlorophenyl)piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-2-ylbenzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenethylpiperazin-1-yl)methanone;-   [4-(2-Chlorophenyl)piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   N-(1-Benzylpyrrolidin-3-yl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(cyclohexylmethyl)piperazin-1-yl]methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-morpholin-4-ylpiperidin-1-yl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-((S)-2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)methanone;-   (3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2-pyridin-3-ylpyrrolidin-1-yl)methanone;-   3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxybenzyl)-N-methylbenzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperazin-1-yl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin-1-yl)methanone;-   [4-(4-Chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   [4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   1-[1-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-1,3-dihydrobenzoimidazol-2-one;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin-1-yl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(1H-indol-3-yl)piperidin-1-yl]methanone;-   (4-Benzhydrylpiperazin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (4-Benzylpiperidin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-1-yl]methanone;-   8-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)methanone;-   [4-(4-Chlorobenzyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-1-yl]methanone;-   (4-Benzoylpiperazin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-furo[3,2-c]pyridin-4-ylpiperazin-1-yl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-pyridin-2-yl-ethyl)benzamide;-   4-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoylamino)piperidine-1-carboxylic    acid ethyl ester;-   N-(1-Benzylpiperidin-4-yl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide;-   1-[4-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]ethanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(1-methylpiperidin-4-yl)benzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethyl)benzyl]benzamide;-   N-[3,5-Bis(trifluoromethyl)benzyl]-4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-thiophen-2-yl-ethyl)benzamide;-   N-Benzhydryl-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-4-ylmethylbenzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-3-ylmethylbenzamide;-   2-[4-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]-N-isopropylacetamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxyethyl)benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)morpholin-4-ylmethanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-naphthalen-1-ylmethylbenzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-1-ylbenzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone;-   N-(2-Chlorobenzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   N-(4-Chlorobenzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   N-(3-Chloro-benzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-phenethylbenzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(3-methoxybenzyl)benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzamide;-   N-Benzyl-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   [4-(3-Chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-2-ylbenzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenethylpiperazin-1-yl)methanone;-   N-Biphenyl-4-ylmethyl-4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   [4-(2-Chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;-   N-(1-Benzylpyrrolidin-3-yl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(cyclohexylmethyl)piperazin-1-yl]methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-((S)-2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)methanone;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2-pyridin-3-yl-pyrrolidin-1-yl)methanone;-   4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxybenzyl)-N-methylbenzamide;-   (4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(1,3-dihydroisoindol-2-yl)methanone;-   {4-[1-(5-Chloro-2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-phenyl}-(spiro[isobenzofuran-1(3H),    4′-piperidine]-1-yl)methanone; and-   1-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one;    or a pharmaceutically acceptable salt form thereof.

In one embodiment, the present invention provides a compound of FormulaI(d) chosen from:

-   1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-Benzyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   (3,4-Dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone;-   (7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone;-   1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile;-   1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid;-   7-Iodo-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   7-Iodo-1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   (2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone;-   1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)-2-phenylethanone;-   2-(2,5-Difluorophenyl)-1-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)ethanone;-   1-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Difluorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-Benzenesulfonyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chlorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile;-   1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic    acid;-   1-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-2-one;-   1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   1-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2,5-Dichlorobenzyl)-7-iodo-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   4-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   6-Bromo-4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;-   7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   7-Iodo-1-[2-(trifluoromethoxy)benzyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;-   7-Iodo-1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;-   1-(2-Chloropyridin-3-ylmethyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;    and-   1-(2-Chloropyridin-3-ylmethyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;    or a pharmaceutically acceptable salt form thereof.

The present invention provides pharmaceutically acceptable salts ofcompounds of Formula I. Pharmaceutically acceptable acid addition saltsof basic compounds of Formula I include, but are not limited to, saltsderived from inorganic acids such as hydrochloric, nitric, phosphoric,sulfuric, hydrobromic, hydriodic, and phosphorus, as well as the saltsderived from organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic-acids, aromatic acids, and aliphatic and aromatic sulfonicacids. Such salts thus include, but are not limited to, sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,caprylate, isobutyrate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate,and methanesulfonate. Also contemplated are the salts of amino acidssuch as arginate, gluconate, galacturonate, and the like; see, forexample, Berge et al., “Pharmaceutical Salts,” J. of PharmaceuticalScience, 1977; 66:1-19.

The acid addition salts of basic compounds of Formula I may be preparedby contacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms can differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but it is expected that the saltsare generally similar to their respective free bases for purposes of thepresent invention.

Pharmaceutically acceptable base addition salts of acidic compounds ofFormula I are formed with metals or amines, such as alkali and alkalineearth metal hydroxides, or of organic amines. Examples of metals used ascations include, but are not limited to, sodium, potassium, magnesium,and calcium. Examples of suitable amines include, but are not limitedto, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine,and procaine; see, for example, Berge et al., supra., 1977.

The base addition salts of acidic compounds of Formula I may be preparedby contacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in a conventional manner. The free acid formscan differ from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but it is expected thatthe salts are generally similar to their respective free acids forpurposes of the present invention.

Some of the compounds in the present invention may exist asstereoisomers, including enantiomers, diastereomers, and geometricisomers. Geometric isomers include compounds of the present inventionthat have alkenyl groups, which may exist as entgegen or zusammenconformations, in which case all geometric forms thereof, both entgegenand zusammen, cis and trans, and mixtures thereof, are within the scopeof the present invention. Some compounds of the present invention havecycloalkyl groups, which may be substituted at more than one carbonatom, in which case all geometric forms thereof, both cis and trans, andmixtures thereof, are within the scope of the present invention. All ofthese forms, including (R), (S), epimers, diastereomers, cis, trans,syn, anti, (E), (Z), tautomers, and mixtures thereof, are contemplatedin the compounds of the present invention.

The compounds to be used in the present invention can exist inunsolvated crystalline forms as well as solvated crystalline forms,including hydrated crystalline forms. In general, the solvated forms,including hydrated forms, are similar to unsolvated forms and areintended to be encompassed within the scope of the present invention.

III. Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising a compound of the present invention (e.g., a compound ofFormula I or a pharmaceutically acceptable salt thereof), together witha pharmaceutically acceptable carrier, diluent, or excipient therefor.Preferably, the pharmaceutical composition contains a therapeuticallyeffective amount of a compound of the present invention. In certainembodiments, these compositions are useful in the treatment of an ALK-or c-Met-mediated disorder or condition. The compounds of the inventioncan also be combined in a pharmaceutical composition that also comprisescompounds that are useful for the treatment of cancer or another ALK- orc-Met-mediated disorder.

A compound of the present invention can be formulated as apharmaceutical composition in the form of a syrup, an elixir, asuspension, a powder, a granule, a tablet, a capsule, a lozenge, atroche, an aqueous solution, a cream, an ointment, a lotion, a gel, anemulsion, etc. Preferably, a compound of the present invention willcause a decrease in symptoms or a disease indicia associated with anALK- or c-Met-mediated disorder as measured quantitatively orqualitatively.

For preparing a pharmaceutical composition from a compound of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component (i.e., compound of the presentinvention). In tablets, the active component is mixed with the carrierhaving the necessary binding properties in suitable proportions andcompacted in the shape and size desired.

The powders and tablets contain from 1% to 95% (w/w) of the activecompound (i.e., compound of the present invention). In certainembodiments, the active compound ranges from 5% to 70% (w/w). Suitablecarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, a low melting wax, cocoa butter, and thelike. The term “preparation” is intended to include the formulation ofthe active compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg,or from 1% to 95% (w/w) of a unit dose, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Pharmaceutically acceptable carriers are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there is a widevariety of suitable formulations of pharmaceutical compositions of thepresent invention (see, e.g., Remington: The Science and Practice ofPharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams andWilkins, 2000).

A compound of the present invention, alone or in combination with othersuitable components, can be made into aerosol formulations (i.e., theycan be “nebulized”) to be administered via inhalation. Aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like.

Formulations suitable for parenteral administration, such as, forexample, by intravenous, intramuscular, intradermal, and subcutaneousroutes, include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and nonaqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. In the practice of this invention,compositions can be administered, for example, by intravenous infusion,orally, topically, intraperitoneally, intravesically or intrathecally.The formulations of compounds can be presented in unit-dose ormulti-dose sealed containers, such as ampoules and vials. Injectionsolutions and suspensions can be prepared from sterile powders,granules, and tablets of the kind previously described.

The dose administered to a subject, in the context of the presentinvention should be sufficient to effect a beneficial therapeuticresponse in the subject over time. The dose will be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician can evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, and/or the progression of thedisease, etc. In general, the dose equivalent of a compound is fromabout 1 μg/kg to 10 mg/kg for a typical subject. Many differentadministration methods are known to those of skill in the art.

For administration, compounds of the present invention can beadministered at a rate determined by factors that can include, but arenot limited to, the LD₅₀ of the compound, the pharmacokinetic profile ofthe compound, contraindicated drugs, and the side-effects of thecompound at various concentrations, as applied to the mass and overallhealth of the subject. Administration can be accomplished via single ordivided doses.

IV. Methods of Treatment

In another aspect, the present invention provides a method of treating asubject suffering from an ALK- or c-Met-mediated disorder or conditioncomprising the step of administering to the subject a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt form thereof. Preferably, the compound of Formula I or apharmaceutically acceptable salt form thereof is administered to thesubject in a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier. In certain embodiments, the ALK- or c-Met-mediatedcondition or disorder is cancer. In certain embodiments, the ALK- orc-Met-mediated condition is selected from anaplastic large celllymphoma, inflammatory myofibroblastic tumor, glioblastoma, and othersolid tumors. In certain embodiments, the ALK- or c-Met-mediatedcondition is selected from colon cancer, breast cancer, renal cancer,lung cancer, hemangioma, squamous cell myeloid leukemia, melanoma,glioblastoma, and astrocytoma.

The ALK- or c-Met-mediated disorder or condition can be treatedprophylactically, acutely, and chronically using compounds of thepresent invention, depending on the nature of the disorder or condition.Typically, the host or subject in each of these methods is human,although other mammals can also benefit from the administration of acompound of the present invention.

In therapeutic applications, the compounds of the present invention canbe prepared and administered in a wide variety of oral and parenteraldosage forms. Thus, the compounds of the present invention can beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the compounds described herein can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. In certain embodiments, thecompounds of the present invention are delivered orally. The compoundscan also be delivered rectally, bucally or by insufflation.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Generally, treatment is initiated with smaller dosageswhich are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect underthe circumstances is reached. For convenience, the total daily dosagemay be divided and administered in portions during the day, if desired.

V. Chemistry

All reagents and solvents were obtained from commercial sources and usedas received. ¹H NMRs were obtained on a Bruker Avance at 400 MHz in thesolvent indicated with tetramethylsilane as an internal standard.Analytical HPLC was run using a Zorbax RX-C8, 5×150 mm column elutingwith a mixture of acetonitrile and water containing 0.1% trifluoroaceticacid with a gradient of 10-100%. LCMS results were obtained on either oftwo instruments. First, in Examples that indicate LCMS retention times,analysis was performed on a Waters Aquity Ultra Performance LC with a2.1 mm×50 mm Waters Aquity HPLC BEH C18 1.7 μm column. The target columntemperature was 45° C., with a run time of two (2) minutes, a flow rateof 0.600 mL/min, and a solvent mixture of 5% (0.1% formicacid/water):95% (acetonitrile/0.1% formic acid). The mass spectrometrydata was acquired on a Micromass LC-ZQ 2000 quadrupole massspectrometer. Second, in Examples that do not indicate LCMS retentiontimes, analysis was performed on a Bruker Esquire 200 ion trap.Automated column chromatography was performed on a CombiFlash Companion(ISCO, Inc.). Melting points were taken on a MeI-Temp apparatus and areuncorrected.

The overall synthesis for compounds of Formula I in which A is nitrogen(i.e., compounds of Formula I(a)) is generically set forth in Scheme 1.

In Step 1,2-amino-5-iodo-3-nitropyridine (A) is converted into itscorresponding diazonium salt (NaNO₂/HCl) in the presence of cuprouschloride to form 2-chloro-5-iodo-3-nitropyridine (B). This process isdescribed in Carroll, F. I. et al., J. Med. Chem., 2002, 45, 4755-4761,which is incorporated herein by reference in its entirety.2-amino-5-iodo-3-nitropyridine is commercially available fromSigma-Aldrich Corp. (St. Louis, Mo.). 2-amino-5-iodo-3-nitropyridine maybe prepared by reacting 2-amino-3-nitropyridine with iodine andhydroiodic acid (See Carroll et al.).

In Step 2, the 2-chloropyridine B obtained in Step 1 is reacted with analpha-amino ester C containing suitable R⁴ and R⁵ groups to form the2-aminopyridine D. An R⁶ group may be introduced in this step (e.g.,R⁶═H, C₁₋₆-alkyl) or in a subsequent step.

In Step 3, compound D is reduced (SnCl₂) and cyclized to form compoundE, which contains the bicyclic pyrido[2,3-b]pyrazinone core.

In Step 4, an R¹-L¹ group is introduced at the amido nitrogen ofcompound E by displacement of the leaving group (LG) from compound F.The product is compound G. Alkylation and acylation reactions useful inStep 4 are described in General Procedures 1 and 2 (below). Examples121, 123, and 124 describe suitable sulfonylation reactions forpreparing compound G in which compound F (R¹-L¹-LG) isR¹—C₀₋₃-alkyl-S(═O)₂—Cl. For compounds in which R¹ is aryl orheteroaryl, and L¹ is a bond, a Buchwald-Hartwig coupling may be used toprepare compound G.

In Step 5, the carbonyl group of compound G is optionally reduced. Areduction reaction useful in Step (5) is described in General Procedure3 (below).

In Step 6, an X group is introduced. Transition metal mediated couplingreactions useful in Step 6 are described in General Procedures 4-6(below). Reactions useful for modifying the introduced X side chain aredescribed in General Procedures 7-10 (below). Compounds of Formula I inwhich X is —C₁₋₃—C(═O)—C₀₋₃-alkyl-G¹L³G²L⁴R⁷ (i.e.,L²=—C₁₋₃—C(═O)—C₀₋₃-alkyl-) can be synthesized by reacting compound Hwith the appropriately substituted ketone and strong base. Compounds ofFormula I in which X is —S(═O), —C₀₋₃-alkyl-G¹L³G²L⁴R⁷ (i.e., L²=—S(═O),—C₀₋₃-alkyl-) or —S(═O)₂NR³⁰—C₀₋₃-alkyl-G¹L³G²L⁴R⁷ (i.e.,L²=—S(═O)₂NR³⁰—C₀₋₃-alkyl-) can be synthesized by reacting compound Hwith an appropriately substituted sulfinic acid. Alternatively,compounds of Formula I in which X is —S(═O), —C₀₋₃-alkyl-G¹L³G²L⁴R⁷ or—S(═O)₂NR³⁰—C₀₋₃-alkyl-G¹L³G²L⁴R⁷ can be synthesized by introducing asulfonyl moiety at the outset of the synthesis, as shown in Scheme 2,optionally followed by reduction of the sulfonyl moiety to form thecorresponding sulfoxide or sulfide.

General Procedure 1—Alkylation

Compound E is suspended in anhydrous N,N-dimethylformamide. NaH (1 eq)is added, forming a solution. A suitable R¹-L¹-LG compound (1 eq) isadded and the resulting reaction stirred at room temperature for 1-4hours. The resulting product (G) is purified by silica gelchromatography. Alkylation selectivity is determined by ¹H NMR NuclearOverhauser Effect (NOE) analysis.

Suitable R¹-L¹-LG compounds for use in this reaction include, but arenot limited to, R¹—C₀₋₃-alkyl-C(═O)—C₁₋₃-alkyl-Br,R¹—C₀₋₃-alkyl-S(═O)_(n)—C₁₋₃-alkyl-Br,R¹—C₀₋₃-alkyl-C(═O)NR¹⁰—C₁₋₃-alkyl-Br,R¹—C₀₋₃-alkyl-S(═O)₂NR¹⁰C₁₋₃-alkyl-Br,R¹—C₀₋₃-alkyl-C(═O)O—C₁₋₃-alkyl-Br,R¹—C₁₋₃-alkyl-OC(═O)NR¹⁰—C₁₋₃-alkyl-Br,R¹—C₀₋₃-alkyl-NR¹⁰—C₁₋₃-alkyl-Br, R¹—C₀₋₃-alkyl-O—C₁₋₃-alkyl-Br,R¹—C₁₋₃-alkyl-Br, C₃₋₁₀-cycloalkyl-Br, heterocycloalkyl-Br, andheteroaryl-Br.

General Procedure 2—Acylation

Compound E is dissolved in anhydrous tetrahydrofuran. Pyridine (1.0 eq)is added, and the solution is cooled to 0° C. A suitable R¹-L¹-LGcompound (1.0 eq) is added dropwise, forming a white precipitate. Thereaction is stirred at 0° C. for 15 minutes, allowed to warm to roomtemperature, and stirred at room temperature for 2-16 hours. Thereaction is diluted with ethyl acetate, washed with NaHCO₃, dried overMgSO₄, filtered, concentrated, and purified by silica gel chromatographyto provide compound G.

Suitable R¹-L¹-LG compounds for use in this reaction include, but arenot limited to, the following R¹-L¹-LG compounds:R¹—C₀₋₃-alkyl-C(═O)—Cl, R¹—C₀₋₃-alkyl-S(═O)₂—Cl,R¹—C₀₋₃-alkyl-OC(═O)—Cl, R¹—C₀₋₃-alkyl-NR¹⁰—C(═O)—Cl, andR¹—C₀₋₃-alkyl-NR¹⁰—S(═O)₂—Cl.

General Procedure 3—Reduction

Compound G is suspended in anhydrous CH₂Cl₂ and cooled to 0° C. DIBAL(8.0 eq) is added and the resulting solution is allowed to warm to roomtemperature over 16 hours. The reaction mixture is quenched withmethanol and a saturated solution of potassium sodium tartrate is added.The resulting mixture is stirred at room temperature until the phasesseparated (about two (2) hours). The organic phase is isolated, driedover MgSO₄, filtered, and concentrated. The product (H; R²,R³═H) ispurified via silica gel chromatography.

General Procedure 4—Suzuki Coupling

-   A. The iodo starting material (H), a suitable boronic acid (R═H) or    boronate ester (R=alkyl) (1.2-2.0 eq), Pd(PPh₃)₄ (0.02-0.05 eq), and    2 M Na₂CO₃ (2.5 eq) are combined in a mixture of toluene/ethanol    (6:1, v/v). The reaction mixture is heated to 80° C. for 1-16 hours.    The reaction mixture is then diluted with CH₂Cl₂, dried over MgSO₄,    filtered, and concentrated. The product (I(a)) is then purified via    silica gel chromatography; or-   B. The iodo starting material (H), a suitable boronic acid or    boronate ester (1.5 eq-2.0 eq), and PdCl₂(PPh₃)₂ (0.1 eq) are    dissolved in tetrahydrofuran (6 mL). Potassium carbonate powder (5.0    eq.) is dissolved in water (6 mL) in a separate flask. The potassium    carbonate solution is added to the boronic acid solution, and the    resulting mixture is purged with nitrogen and stirred at 70° C. for    one (1) hour. The reaction mixture is concentrated, and methylene    chloride and water are added. The organic phase is isolated, washed    with saturated sodium bicarbonate solution and brine, dried with    magnesium sulfate, filtered and concentrated. The product of Formula    I(a) is then purified by normal phase column chromatography.

Suitable boronic acids or boronate esters include, but are not limitedto, those in which the X group of the X—B(OR)₂ reagent is linked to theboron atom of the X—B(OR)₂ reagent via an alkyl, aryl, heteroaryl, oralkenyl C—B bond.

Alternative reaction conditions include, but are not limited to, thefollowing:

-   -   (a) Reaction of a heteroaryl boronic acid with compound H in        dioxane/water (2:1) at 100° C. for 18 hours in the presence of        Pd₂(dibenzylideneacetone)₃ (1 mol-%), P(cyclohexyl)₃ (2.4 mol-%)        and K₃PO₄ (1.7 eq). (See Kudo, N. et al., Angew. Chem. Int. Ed.,        2006, 45, 1282-1284); and    -   (b) Reaction of a vinyl or alkenyl boronic acid with compound H        in tert-amyl alcohol at room temperature for 24 hours in the        presence of Pd(acetate)₂ (5 mol-%), P(tert-butyl)₂CH₃ or        [HP(tert-butyl)₂CH₃]BF₄ (0.1 eq) and KOtert-butyl (3 eq). (See        Kirchhoff, J. H. et al., J. Am. Chem. Soc., 2002, 124,        13662-13663).        General Procedure 5—Sonogashira Coupling

The iodo starting material (H), a suitable terminal alkyne (20 mg),tetrakis(triphenylphosphine) palladium (0.045 eq.), copper (I) iodide (9mg), triethylamine (0.5 mL) and anhydrous tetrahydrofuran (1 mL) arecombined in a Schlenk flask. The solution is purged with nitrogen,evacuated, stirred under nitrogen for 16 hours. The reaction mixture isconcentrated, diluted with CH₂Cl₂, washed with H₂O, dried with magnesiumsulfate, filtered and concentrated. The product is then purified bynormal phase column chromatography.

The product may be converted to the corresponding alkenyl and alkylcompounds of Formula I(a) by reduction of the triple bond (e.g.,catalytic hydrogenation or Na/NH₃).

General Procedure 6—Rosenmund-von Braun Coupling

The iodo starting material H is dissolved in anhydrousN,N-dimethylformamide. CuCN (2.0 eq) is added and the reaction mixtureis heated to 120° C. in a microwave oven for 15 minutes. The reactionmixture is concentrated, diluted with CH₂Cl₂, and washed with H₂O/NH₄OH(10:1, v/v) to remove copper. The mixture is then filtered. The organicphase is dried over MgSO₄, filtered, and concentrated. The product ispurified by silica gel chromatography.

As shown in Scheme 3, the —CN group of the product is a useful buildingblock, which can be converted by standard chemical processes into avariety of linker groups (L²). Examples include, but are not limited to,—C(═O)—C₀₋₃-alkyl-, —C(═O)NR¹⁰—C₀₋₃-alkyl-, —C(═O)O—C₀₋₃-alkyl-,—CH₂—OC(═O)NR¹⁰—C₀₋₃alkyl-, —CH₂—NR¹⁰C(═O)O—C₀₋₃-alkyl-,—CH₂—NR¹⁰—C₀₋₃-alkyl-, —CH₂—O—C₀₋₃-alkyl-, —CH₂—OC(═O)—C₀₋₃alkyl-,—CH₂—NR¹⁰C(═O)—C₀₋₃-alkyl-, and —CH₂—NR¹⁰S(═O)₂—C₀₋₃-alkyl-. (SeeFleming, F. F. et al., Tetrahedron, 2005, 61, 747).

General Procedure 7—Saponification

A suitable aryl ester starting material is heated with LiOH·H₂O (5 eq)in a mixture of tetrahydrofuran and H₂O (1:1, v/v) at 70° C. for 2 to 16hours. The resulting solution is concentrated and neutralized with 1 NHCl. The resulting precipitate is filtered to obtain the product arylcarboxylic acid.

General Procedure 8—Amidation

A suitable aryl carboxylic acid starting material is combined withN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.0 eq),1-hydroxybenzotriazole (1.7 eq), and triethylamine (1.4 eq) in anhydrousN,N-dimethylformamide. The resulting mixture is stirred at roomtemperature for 30 minutes, a suitable amine is added, and the mixtureis stirred for 3-16 hours. The reaction mixture is then concentrated,diluted with CH₂Cl₂, washed with H₂O, and dried over MgSO₄. The productamide is purified via silica gel chromatography or reversed-phasepreparative HPLC.

The amidation reaction of General Procedure 8 may also be used toprepare amide boronates for use in the Suzuki coupling reaction (GeneralProcedure 4). For example, Scheme 4 shows the amidation of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzoic acid, which iscommercially available from Sigma-Aldrich Corp. (St. Louis, Mo.), byreaction with 4-(pyrrolidin-1-yl)piperidine using the reactionconditions of General Procedure 8.

Scheme 4. Synthesis of Amide Boronates

General Procedure 9—Hydrolysis

A suitable cyano starting material is suspended in a mixture of NaOH (10N), H₂O, and ethanol (1:1:1, v/v/v) and heated to 80° C. for 16 hours.The reaction mixture is diluted with H₂O and neutralized with HCl. Theresulting carboxylic is isolated (e.g., by filtration).

General Procedure 10—Amidation

To a mixture of a suitable carboxylic acid starting material (1.3 eq) inanhydrous dimethylacetamide (DMA, 0.3 mL) is added polystyrene-supporteddicyclohexylcarbodiimide (DCC, 6.0 eq) followed by a solution ofN-hydroxybenzotriazole in DMA (300 mM, 1.5 eq). The reaction mixture isthoroughly mixed and allowed to stand at room temperature for 15minutes. The reaction mixture is then treated with a 0.10 M solution ofa suitable amine (1.0 eq) and heated with 250 W microwave pulses to 60°C. The reaction mixture is then cooled to room temperature and treatedwith resin bound macroporous carbonate (acid scavenger) overnight. Thereaction mixture is filtered, the solid is washed twice with DMA (200μL) followed by acetonitrile (200 μL). The combined washes areevaporated under reduced pressure to afford the amide product.

General Procedure 11—Sulfonamide Boronate Synthesis

4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (J) isdissolved in CH₂Cl₂ and N-methyl morpholine (3 eq) is added. Thereaction mixture is cooled to 0° C. and 2-chloroethanesulfonyl chloride(1.1 eq) is added dropwise. The reaction mixture is allowed to warm toroom temperature and stirred for four (4) hours. The reaction mixture isthen concentrated, diluted with ethyl acetate, washed with brine, driedover MgSO₄, concentrated, and purified through silica gelchromatography. The resulting ethenesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide (K) isdissolved in methanol and a suitable amine (2.5 eq) is added inmethanol. The reaction mixture is stirred at room temperature for four(4) hours. Isocyanate resin is added to each vial to consume excessamine. After stirring overnight, the resin is filtered and the reactionsolution concentrated to afford the desired sulfonamide boronate (L).

The overall scheme used to prepare compounds of Formula I in which A iscarbon (i.e., compounds of Formula I(b)) is generically set forth inSchemes 5-12.

In Step 1, 2-amino-5-bromopyridine (M) is converted to3-(6-bromo-pyridin-2-ylamino)propionic acid (O) by reaction with ethylacrylate (N). This process is described in Settimo, D. A. et al., IlFarmaco—Ed. Sc., 1978, 33(10), 770-80, which is incorporated herein byreference in its entirety. 2-amino-5-bromopyridine is commerciallyavailable from Sigma-Aldrich Corp. (St. Louis, Mo.).

In Step 2, the aryl carboxylic acid O is treated with Eaton's reagent toafford 7-bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one (P).

In Step 3, compound P is reduced (NaBH₄), debrominated (n-BuLi), andrebrominated (N-bromosuccinimide) to form compound Q. Optionally, thecarbonyl group of compound P can be converted to an enolate and thensubstituted with R²/R³ groups prior to the reduction reaction.Optionally, compound P can be transformed into the correspondingα,β-unsaturated ketone (e.g., by conversion to an α-selenoxide orα-sulfoxide intermediate followed by elimination) and then substitutedat the β-position with R⁴/R⁵ groups (e.g., via a Michael additionreaction) prior to the reduction reaction. Optionally, an R⁶ group canbe introduced (e.g., by N-alkylation) prior to the reduction reaction.Compound Q may be converted to a compound of Formula I(b) by steps 4 and5 or 4′ and 5′.

In Step 4, compound Q is converted to compound R by introduction of anR¹-L¹ group. The conversion may be accomplished by a variety of methodsknown to those of ordinary skill in the art. For example, the benzylichydroxyl group of compound Q may be activated by conversion to thecorresponding tosylate, mesylate, triflate, or halide intermediate andthen displaced with a nucleophilic R¹-L¹ group or a nucleophilicderivative of a R¹-L¹ group, such as an organolithium or organometallicderivative (e.g., Grignard, lithium, lithium dialkylcopper, aluminum, orboron derivatives) (See March, J., “Advanced Organic Chemistry,” 3d ed.,John Wiley & Sons, Inc., 1985, pp. 400-404, 407; Luh, T-Y et al., Chem.Rev., 2000, 100, 3187-3204) (See Scheme 6). A displacement reactionuseful in Step 4 is described in General Procedure 12 (below).

In addition, Step 4 may be performed by coupling the hydroxyl group ofcompound Q to a suitable carbonyl chloride reagent. Suitable carbonylchloride reagents include, but are not limited to,Cl—C(═O)—C₀₋₃-alkyl-R¹ and Cl—C(═O)NR¹⁰—C₀₋₃-alkyl-R¹, which result inproducts of Formula R in which L¹-R¹ is —OC(═O)—C₀₋₃-alkyl-R¹ and—OC(═O)NR¹⁰—C₀₋₃-alkyl-R¹, respectively.

In Step 5, compound R is converted to a compound of Formula I (A=carbon)by introduction of an X group. The conversion may be performed using atransition metal mediated coupling reaction (met=Pd, Cu, etc.). Acoupling reaction useful in Step 4′ is described in General Procedure 13(below). The coupling reactions in General Procedures 4, 5, and 6(above) are also useful for preparing the corresponding compounds ofFormula I(b).

Steps 4′ and 5′ are the same as Steps 5 and 4, respectively.

In the first step, compound Q is reacted with p-toluenesulfonyl chloride(tosyl chloride) to form the activated tosylate XX. Other activatinggroups that can be used instead of tosylate include, but are not limitedto, mesylate, triflate, and halide.

In the second step, compound XX is reacted with a suitable Grignardreagent (R¹L¹-MgBr) or another suitable organometallic reagent to formcompound R. Suitable organometallic reagents include, but are notlimited to, R¹-L¹-Li, R¹-L¹-MgBr, and (R¹-L¹)₂CuLi, wherein R¹-L¹- is—C₁₋₃-alkyl-C(═O)—C₀₋₃-alkyl-R¹, —C₁₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-R¹,—C₁₋₃-alkyl-C(═O)NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-C(═O)NR¹⁰—C₁₋₃-alkyl-,—C₁₋₃-alkyl-S(═O)₂NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-S(═O)₂NR¹⁰—C₁₋₃-alkyl-, —C₁₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-C(═O)O—C₁₋₃-alkyl-, —C₁₋₃-alkyl-OC(═O)NR¹⁰—C₀₋₃-alkyl-R¹,R¹—C₀₋₃-alkyl-OC(═O)NR¹⁰—C₁₋₃-alkyl-, —C₁₋₃-alkyl-NR¹⁰—C₀₋₃-alkyl-R¹,—C₁₋₃-alkyl-O—C₀₋₃-alkyl-R¹, —C₁₋₆-alkyl-R¹, —C₂₋₆-alkenyl-R¹, or—C₂₋₆-alkynyl-R¹.

In Step 1, compound P (Scheme 5) is converted to compound T by means ofa Takai reaction. Optionally, the carbonyl group of compound P can beconverted to an enolate and then substituted with R²/R³ groups prior tothe Takai reaction. Optionally, compound P can be transformed into thecorresponding α,β-unsaturated ketone (e.g., by conversion to anα-selenoxide or α-sulfoxide intermediate followed by elimination) andthen substituted at the β-position with R⁴/R⁵ groups (e.g., via aMichael addition reaction) prior to the Takai reaction. Optionally, anR⁶ group can be introduced (e.g., by N-alkylation) prior to the Takaireaction.

In Step 2, compound T is converted to compound U via a transition metalcatalyzed coupling reaction (e.g., a Suzuki reaction).

In Step 3, compound U is hydrogenated and debrominated by hydrogenolysisto form compound V.

In Step 4, compound V is brominated to form compound W.

In Step 5, compound W is converted to compound I(e) via a transitionmetal catalyzed coupling reaction (See General Procedures 4-6 and 13).

In Step 1, compound P (Scheme 5) is converted to an imine or iminium ofFormula AA by means of a condensation reaction with an amine of formulaZ-NH—R¹⁰. Optionally, the carbonyl group of compound P can be convertedto an α-enolate and then substituted at the α-position with R²/R³ groupsprior to the condensation reaction. Optionally, compound P can betransformed into the corresponding α,β-unsaturated ketone (e.g., byconversion to an α-selenoxide or α-sulfoxide intermediate followed byelimination) and then substituted at the β-position with R⁴/R⁵ groups(e.g., via a Michael addition reaction) prior to the condensationreaction. Optionally, an R⁶ group can be introduced (e.g., byN-alkylation) prior to the condensation reaction.

In Step 2, compound AA is converted to compound BB by means of areduction. Steps 1 and 2 may be combined into a single step (i.e. areductive amination).

In Step 3, compound BB is converted to compound CC by means ofdebromination/rebromination (e.g., as in Scheme 5, Step 3).

In addition, when Z=H the —NHR¹⁰ group of compound BB may be coupled toa suitable carbonyl or sulfonyl chloride reagent to form additionalcompounds of Formula CC. Suitable carbonyl or sulfonyl chloride reagentsinclude, but are not limited to, R¹—C₀₋₃-alkyl-C(═O)—Cl,R¹—C₀₋₃-alkyl-S(═O)₂—Cl, or R¹—C₀₋₃-alkyl-OC(═O)—Cl, which result inproducts of Formula CC in which L¹-R¹ is R¹—C₀₋₃-alkyl-C(═O)NR¹⁰—,R¹—C₀₋₃-alkyl-S(═O)₂NR¹⁰—, or R¹—C₀₋₃-alkyl-OC(═O)NR¹⁰—, respectively.

In Step 4, compound CC is converted to compound I(f) (e.g., as in Scheme5, Step 5).

Alternatively, in Step 1′, compound CC may be prepared from compound Qby activation of compound Q (e.g., by transformation to thecorresponding benzylic halide, alkyl sulfonate or aryl sulfonate as inScheme 5, Step 4) prior to treatment with an amine of formula Z-NH—R¹⁰.

In Step 1, compound P (Scheme 5) is converted to compound DD by means ofa Horner-Emmons reaction. Optionally, R², R³, R⁴, R⁵ and/or R⁶ groupsmay be introduced prior to the Horner-Emmons reaction as in Scheme 8.

In Step 2, compound DD is converted to compound EE by means ofhydrogenation of the double bond and debromination by hydrogenolysis ormetallation/protonation (Scheme 5, Step 3).

In Step 3, compound EE is brominated and hydrolyzed to form compound FF.Optionally, compound FF may be alkylated α to the carbonyl group priorto the coupling step with one or two methyl groups or an ethyl group(e.g., by treatment with base and then methyl bromide).

In Step 4, compound FF is coupled with an amine of formula Z-NH—R¹⁰ toform compound GG.

In Step 5, compound GG is converted to compound I(g) (e.g., as in Scheme5, Step 5).

In Step 1, compound FF (Scheme 9) is esterified with Z-OH to formcompound HH.

In Step 2, compound HH is converted to compound I(h) (e.g., as in Scheme5, Step 5).

Optionally, compound FF or HH may be alkylated α to the carbonyl groupprior to Steps 1 or 2 with one or two methyl groups or an ethyl group(e.g., by treatment with base and then methyl bromide).

In Step 1, compound Q (Scheme 5) is activated by means of transformationto the benzylic halide, alkyl sulfonate or aryl sulfonate prior totreatment with a thiol of formula Z-SH to form compound JJ.Alternatively, activated compound Q may be treated with a sulfinic acidof formula Z-SO₂H to form the sulfone analog of compound JJ.

In Step 2, the bromide group of compound JJ is converted to the X groupof compound I(i) (e.g., as in Scheme 5, Step 5). Optionally, the sulfidegroup of compound JJ may be oxidized to the sulfoxide (n=1) or sulfone(n=2) before or after conversion of Br to X.

In Step 1, compound EE (Scheme 9) is converted to compound KK byreaction with an organometallic reagent such as a Grignard ororganolithium reagent (e.g., Z-MgBr or Z-Li).

In Step 2, compound KK is converted to compound I(j) (e.g., as in Scheme5, Step 5).

Optionally, compound EE or KK may be alkylated α to the carbonyl groupprior to Steps 1 or 2 with one or two methyl groups or an ethyl group(e.g., by treatment with base and then methyl bromide).

General Procedure 12—Mitsunobu Reaction

The starting benzyl alcohol (Q or S) (1 eq) is combined with a suitablenucleophile (R¹L¹:) (1-3.0 eq) and triphenylphosphine (1-3.0 eq) inanhydrous tetrahydrofuran. Diisopropylazodicarboxylate (3.0 eq) is addedand the reaction mixture stirred at room temperature for 15 minutes. Themixture is then concentrated under reduced pressure and purified bysilica gel chromatography to afford the desired product (R or I(b)).

General Procedure 13—Suzuki Coupling

The starting bromide (Q or R) (1.0 eq) is combined with a suitableboronic acid or boronic ester (1.4 eq) and Pd(PPh₃)₄ (0.05 eq) in amixture of toluene and ethanol (1-5:1, v/v). Sodium carbonate Na₂CO₃(2N, 4.0 eq) is added and the reaction mixture is heated at 80-100° C.for 0.5 to 24 hours. Two purification procedures may be followed. In thefirst procedure, the mixture is concentrated under reduced pressure, andthe residue is taken up in methylene chloride and washed with water. Theorganic phase is dried over sodium sulfate, filtered, and concentratedunder reduced pressure, and purified by silica gel chromatography toafford the desired product (S or I(b)). In the second procedure, thecrude reaction mixture is cooled, directly concentrated onto silica gel,and purified by silica gel chromatography to afford the desired product(S or I(b)).

VI. Biology

ALK Kinase Assay

Example compounds were tested for their ability to inhibit the kinaseactivity of baculovirus-expressed ALK using a modification of the ELISAprotocol reported for trkA in Angeles, T. S. et al., Anal. Biochem.1996, 236, 49-55, which is incorporated herein by reference in itsentirety. Phosphorylation of the substrate, phospholipase C-gamma(PLC-γ) generated as a fusion protein with glutathione S-transferase(GST) as reported in Rotin, D. et al., EMBO J. 1992, 11, 559-567, whichis incorporated herein by reference in its entirety, was detected with aeuropium-labeled anti-phosphotyrosine antibody and measured bytime-resolved fluorescence (TRF). Briefly, each 96-well plate was coatedwith 100 μL/well of 10 μg/mL substrate (phospholipase C-γ) inTris-buffered saline (TBS). The assay mixture (total volume=100 μL/well)consisting of 20 mM HEPES (pH 7.2), 1 μM ATP (K_(m) level), 5 mM MnCl₂,0.1% BSA, 2.5% DMSO, and various concentrations of test compound wasthen added to the assay plate. The reaction was initiated by addingenzyme (30 ng/ml ALK) and was allowed to proceed at 37° C. for 15minutes. Detection of the phosphorylated product was performed by adding100 μl/well of Eu-N1 labeled PT66 antibody (Perkin Elmer # AD0041).Incubation at 37° C. then proceeded for one (1) hour, followed byaddition of 100 μL enhancement solution (Wallac #1244-105). The platewas gently agitated and after thirty minutes, the fluorescence of theresulting solution was measured using the EnVision 2100 (or 2102)multilabel plate reader (Perkin Elmer).

Data analysis was performed using ActivityBase (IDBS, Guilford, UK).IC₅₀ values were calculated by plotting percent inhibition versus log₁₀of the concentration of compound and fitting to the nonlinear regressionsigmoidal dose-response (variable slope) equation in XLFit (IDBS,Guilford, UK).

c-Met Kinase Assay

The kinase activity of c-Met was evaluated using the same methods as forALK, with the following modifications: Plates were coated with 20 μg/mLphospholipase C-γ and the assay mixture consisted of 50 mM HEPES (pH7.2), 50 mM NaCl, 3 μM ATP (K_(m) level), 4 mM MnCl₂, 0.01% TritonX-100,0.02% BSA, 2.5% DMSO. Reactions were initiated with 30 ng/mL c-Met(cytoplasmic domain, Invitrogen Corporation #PV3143).

ALK Cellular Assay

Immunoblotting of phospho-NPM-ALK and total NPM-ALK from cell lysateswas carried out according to the protocols provided by the antibodysuppliers. In brief, after treatment of Example compounds, cells werelysed in Frak lysis buffer [10 mM Tris, pH 7.5, 1% Triton X-100, 50 mMsodium chloride, 20 mM sodium fluoride, 2 mM sodium pyrophosphate, 0.1%BSA, plus freshly prepared 1 mM activated sodium vanadate, 1 mMdithiothreitol (#165680050, ARCOS Organics, Geel, Belgium), and 1 mMPMSF (#837091, Boehringer Mannheim Biochemicals, Indianapolis, Ind.),protease inhibitors cocktail III (#539134-1Set, Calbiochem, 1:100dilution)]. After brief sonication, the lysates were cleared bycentrifugation, mixed with sample buffer and subjected to SDS-PAGE.Following transfer to membranes, the membranes were blotted with eitherrabbit phospho-NPM-ALK(Y664) (Cat^(#)3341) or ALK antibody (Cat^(#)3342)from Cell Signaling Technology (Beverly, Mass.), and then theHRP-conjugated goat anti-rabbit antibodies (Santa Cruz, Calif.) afterwashed in TBS/0.2% Tween-20. The protein bands were visualized with ECLWestern Blotting detection reagents (RPN2106, Amersham Biosciences,Buckinghamshire, UK) and quantitated with gel-pro analyzer 3.1 software.

To measure ALK tyrosine phosphorylation in cells with an ELISA assay,fluoronunc plates (Cat^(#)437796, Nalge Nunc, Rochester, N.Y.) werepre-coated with goat anti-mouse IgG, and incubated with the capturemouse ALK antibody (Cat^(#)35-4300, Zymed, Seattle, Wash.) diluted1:1000 in Superblock (Pierce, Rockford, Ill.). Following blocking, celllysates were added to plates and incubated overnight at 4° C. Plateswere incubated with the detecting antibody, anti-phospho-ALK (Y664)(Cell Signaling Technology), diluted at 1:2000, followed by incubationwith goat anti-rabbit-IgG alkaline phosphatase to amplify the detection.Wells were exposed to the fluorogenic substrate 4-MeUP (#3368-04-5,Calbiochem) and the signal quantified using a CytoFluor® (series 4000)Fluorescence Multi-Well Plate Reader (Applied Biosystems, Foster City,Calif.).

c-Met Cellular Assay

HT29 and GTL-16 cells were serum starved for one hour in mediacontaining 0.05% BSA and varying concentrations of Example compounds(1-10 μM). A549 cells were serum starved overnight in media containing0.05% BSA then treated for one hour with Example compounds followed by a15 minute stimulation with 50 ng/mL HGF (Peprotech, Rocky Hill, N.J.),respectively. Samples were resolved by electrophoresis on a 3-8%Tris-Acetate gel (40 ma/gel) and then transferred to a nitrocellulosemembrane. Membranes were blocked for one hour at room temperature inOdyssey Blocking Buffer (Licor #927-40000) diluted 1:1 with 1×TBS.Membranes were then co-incubated overnight at 4° C. with primaryantibodies [total Met (Cell Signaling, #3127) and Phospho-Met(Biosource, #44-888G) 1:1000 each in Odyssey Blocking Buffer diluted 1:1with 1×TBS-T 0.05%]. The next day, membranes were washed andco-incubated with secondary antibodies [Goat anti mouse IRDye800(Rockland, #610-132-121) and Goat anti rabbit Alexa fluor 700 (MolecularProbes, #A21038) 1:10,000] in Odyssey Blocking Buffer diluted 1:1 with1×TBS-T 0.05% for one hour at room temperature protected from light.Blots were then washed and read on the Odyssey Infrared Imager. Totalc-Met signal was visualized at 800 nm detection and phospho-c-Met signalwas visualized at 700 nm detection.

Results

Biological data for the Example compounds is presented in the followingTables 1-3.

IC₅₀ > 100 μM − IC₅₀ 100 μM-10 μM + IC₅₀ 10 μM-1 μM ++ IC₅₀ 1 μM-0.1 μM+++ IC₅₀ < 0.1 μM ++++ Not tested NT

TABLE 1 ALK, c-Met Kinase Inhibition Example c-Met ALK 1 + + 2 − − 3 − +4 + ++ 5 − ++ 6 + +++ 7 + ++ 8 − + 9 − + 10 − + 11 + + 12 + ++ 13 − + 14− + 15 + ++ 16 + ++ 17 + + 18 + ++ 19 + ++ 20 + ++ 21 − + 22 − − 23 + ++24 − ++ 25 + ++ 26 + ++ 27 + + 28 − − 29 + +++ 30 + ++ 31 + − 32 − − 33− + 34 + ++ 35 − ++ 36 ++ +++ 37 + ++ 38 +++ +++ 39 + ++ 40 − − 41 − −42 − − 43 + − 44 + − 45 − ++ 46 + + 47 + + 48 ++ +++ 49 + +++ 50 − +++51 + +++ 52 + + 53 + − 54 + − 55 − + 56 + ++ 57 +++ +++ 58 + +++ 59 ++++ 60 ++ +++ 61 ++ +++ 62 + ++ 63 − +++ 64 + +++ 65 ++ ++++ 66 ++ ++++67 ++ +++ 68 ++ +++ 69 ++ ++++ 70 + +++ 71 − +++ 72 ++ +++ 73 + +++74 + + 75 + +++ 76 ++ +++ 77 − ++ 78 − − 79 − + 80 − + 81 − − 82 + −83 + ++ 84 ++ +++ 85 + + 86 ++ ++ 87 − − 88 ++ + 89 + + 90 − − 91 + − 92− − 93 − − 94 + ++ 95 + ++ 96 + ++ 97 − + 98 − ++ 99 +++ ++++ 100 +++++++ 101 ++ +++ 102 ++ +++ 103 + +++ 104 +++ ++++ 105 ++ ++++ 106 ++++++ 107 + ++++ 108 + ++++ 109 − + 110 + − 111 + − 112 + + 113 + ++114 + ++ 115 − ++ 116 − + 117 ++ ++++ 118 ++ ++++ 119 − − 120 ++ +++121 + ++ 122 ++ +++ 123 + + 124 + ++ 125 + +++ 126 ++ +++ 127 − ++ 128 +− 129 + +++ 130 + ++ 131 ++ ++ 132 ++ ++++ 133 − − 134 + + 135 − − 136 −− 137 − + 138 + ++ 139 + + 140 ++ ++ 141 ++ +++ 142 ++ +++ 143 ++ +++144 ++ +++ 145 − − 146 + − 147 − + 148 + +++ 149 − − 150 − − 151 + +++152 + ++ 153 − − 154 + ++++ 155 − + 156 +++ ++++ 157 +++ ++++ 158 − ++159 ++ ++++ 160 +++ ++++ 161 +++ +++ 162 + ++ 163 +++ ++++ 164 ++ ++++165 − +++ 166 − +++ 167 + +++ 168 + ++ 169 + +++ 170 − ++ 171 − + 172 ++++ 173 ++ ++ 174 + +++ 175 − − 176 + ++ 177 ++ ++++ 178 + − 179 − − 180++ ++++ 181 ++ +++ 182 NT NT 183 ++ +++ 184 ++ ++++ 185 +++ ++++ 186 ++++++ 187 − − 188 − ++ 189 +++ ++++ 190 +++ ++++ 191 +++ +++ 192 +++ ++++193 − − 194 − +++ 195 ++ ++ 196 + ++ 197 ++ +++ 198 +++ ++++ 199 ++ ++++200 ++ +++ 201 NT NT 202 + +++ 203 ++ +++ 204 + +++ 205 ++ ++++ 206 − +207 − ++ 208 − ++ 209 + ++ 210 + ++ 211 + + 212 ++ ++ 213 + ++ 214 + +215 + + 216 − ++ 217 − ++ 218 + + 219 + ++ 220 ++ ++ 221 − + 222 + + 223− ++ 224 + ++ 225 + ++ 226 + + 227 + + 228 + ++ 229 ++ ++ 230 − ++ 231 +++ 232 − +++ 233 + ++ 234 − ++ 235 + ++ 236 + ++ 237 ++ ++ 238 − ++ 239− ++ 240 − +++ 241 − +++ 242 − ++ 243 + + 244 − ++ 245 + +++ 246 − +++247 − ++ 248 − ++ 249 − + 250 − +++ 251 + + 252 − + 253 − +++ 254 − ++255 − ++ 256 − ++ 257 − + 258 − ++ 259 − ++ 260 − ++ 261 − ++ 262 − +263 − ++ 264 − ++ 265 − − 266 − − 267 − + 268 − − 269 + − 270 − − 271 +− 272 ++ +++ 273 + + 274 ++ ++ 275 ++ + 276 + + 277 + + 278 ++ ++ 279 +++ 280 + ++ 281 ++ +++ 282 NT NT 283 − − 284 NT NT 285 NT NT 286 − ++287 +++ ++++ 288 + +++ 289 +++ ++++ 290 − + 291 − + 292 − ++ 293 ++ ++294 + + 295 ++ ++++ 296 NT NT 297 − ++ 298 − ++ 299 − ++ 300 NT NT 301NT NT 302 − − 303 − − 304 − ++ 305 ++ ++++ 306 NT +++ 307 NT +++ 308 NT+++ 309 NT +++ 310 NT +++ 311 NT +++ 312 NT +++ 313 NT +++ 314 NT +++315 NT ++ 316 NT +++ 317 NT +++ 318 NT +++ 319 NT +++ 320 NT +++ 321 NT+++ 322 NT +++ 323 NT +++ 324 NT +++ 325 NT +++ 326 NT +++ 327 NT ++++328 NT +++ 329 NT ++++ 330 NT +++ 331 NT ++ 332 NT +++ 333 NT +++ 334 NT++++ 335 NT +++ 336 NT +++ 337 NT +++ 338 NT +++ 339 NT +++ 340 NT +++341 NT +++ 342 NT +++ 343 NT +++ 344 NT +++ 345 NT +++ 346 NT +++ 347 NT+++ 348 NT +++ 349 NT +++ 350 NT ++ 351 NT +++ 352 NT +++ 353 NT ++ 354NT +++ 355 NT +++ 356 NT +++ 357 NT +++ 358 NT +++ 359 NT +++ 360 NT +++361 NT ++++ 362 NT +++ 363 NT +++ 364 NT +++ 365 NT ++++ 366 NT +++ 367NT +++ 368 NT +++ 369 NT +++ 370 NT +++ 371 NT +++ 372 NT +++ 373 NT +++374 NT +++ 375 NT +++ 376 NT +++ 377 NT ++ 378 NT ++ 379 NT +++ 380 NT+++ 381 NT +++ 382 NT +++ 383 NT +++ 384 NT +++ 385 NT ++++ 386 NT +++387 NT +++ 388 NT +++ 389 NT +++ 390 NT +++ 391 NT +++ 392 NT ++++ 393NT ++++ 394 NT ++++ 395 NT +++ 396 NT +++ 397 NT +++ 398 NT +++ 399 NT++ 400 NT +++ 401 NT +++ 402 NT ++++ 403 NT ++++ 404 NT ++++ 405 NT +++406 NT ++++ 407 NT +++ 408 NT +++ 409 NT ++ 410 NT +++ 411 NT +++ 412 NT+++ 413 NT +++ 414 NT +++ 415 NT ++++ 416 NT +++ 417 NT +++ 418 NT +++419 NT +++ 420 NT +++ 421 NT +++ 422 NT +++ 423 NT +++ 424 NT +++ 425 NT++ 426 NT +++ 427 NT +++ 428 NT ++ 429 NT +++ 430 NT ++++ 431 NT +++ 432NT +++ 433 NT +++ 434 NT +++ 437 ++ +++

Preferably, the compounds of the present invention exhibit an IC₅₀ inthe ALK kinase assay of 100 μM-10 μM. More preferably, the compounds ofthe present invention exhibit an IC₅₀ in the ALK kinase assay of 10 μM-1μM. More preferably, the compounds of the present invention exhibit anIC₅₀ in the ALK kinase assay of 1 μM-0.1 μM. More preferably, thecompounds of the present invention exhibit an IC₅₀ in the ALK kinaseassay of <0.1 μM.

Preferably, the compounds of the present invention exhibit an IC₅₀ inthe c-Met kinase assay of 100 μM-10 μM. More preferably, the compoundsof the present invention exhibit an IC₅₀ in the e-Met kinase assay of 10μM-1 μM. More preferably, the compounds of the present invention exhibitan IC₅₀ in the c-Met kinase assay of 1 μM-0.1 μM. More preferably, thecompounds of the present invention exhibit an IC₅₀ in the c-Met kinaseassay of <0.1 μM.

TABLE 2 c-Met Cellular Activity/Autophosphorylation Assay* HT29 HT29A549 A549 GTL-16 GTL-16 Cells Cells Cells Cells Cells Cells Example (1μM) (3 μM) (1 μM) (3 μM) (1 μM) (3 μM) 69 1 1 1 1 72 2 2 1 1 76 1 2 1 199 1 1 1 1 100 1 1 1 1 102 2 3 1 2 104 1 3 117 1 1 118 2 3 1 2 120 2 2 12 122 2 2 1 2 157 1 2 1 1 159 1 1 1 1 160 2 2 1 1 163 1 2 1 1 164 1 1 11 168 1 2 1 1 177 2 2 1 1 184 3 4 185 3 4 1 1 186 2 2 1 1 190 1 1 287 12 1 1 *Inhibition scores: 1, 0-25%; 2, 26-50%; 3, 51-75%; 4, 76-100%

Preferably, the compounds of the present invention exhibit an inhibitionscore in the c-Met Cellular Assay of 26-50%. More preferably, thecompounds of the present invention exhibit an inhibition score in thec-Met Cellular Assay of 51-75%. More preferably, the compounds of thepresent invention exhibit an inhibition score in the c-Met CellularAssay of 76-100%.

TABLE 3 ALK Cellular Activity ALK Cellular Activity Example InhibitionScore at 1 μM* ALK Cellular Activity** 6 1 38 ++ 48 2 51 2 57 1 58 1 65++++ 66 ++++ 69 + 99 ++++ 100 ++++ 105 + 106 ++++ 117 ++++ 118 ++++ 132+++ 141 3 144 1 154 +++ 156 +++ 157 +++ 159 +++ 160 ++++ 163 + 164 +++177 +++ 180 +++ 186 ++++ 189 ++++ 190 ++ 198 ++++ 199 ++++ 200 + 205 +++295 +++ *Inhibition scores: 1, 0-25%; 2, 26-50%; 3, 51-75%; 4, 76-100%**IC₅₀ > 1000 nM − IC₅₀ 751 nM-1000 nM + IC₅₀ 501 nM-750 nM ++ IC₅₀ 251nM-500 nM +++ IC₅₀ ≦ 250 nM ++++

Preferably, the compounds of the present invention exhibit an inhibitionscore in the ALK Cellular Assay of 26-50%. More preferably, thecompounds of the present invention exhibit an inhibition score in theALK Cellular Assay of 51-75%. More preferably, the compounds of thepresent invention exhibit an inhibition score in the ALK Cellular Assayof 76-100%.

EXAMPLES Preparation 1.(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]amide

A solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (X) (15.12g, 69 mmol) in CH₂Cl₂ (600 mL) was treated with pyridine (5.46 g, 69mmol) and cooled in an ice bath. p-Nitrophenylchloroformate (14.00 g,69.5 mmol) was added, the ice bath was removed, and the reaction wasstirred overnight. The mixture was poured into a separatory funnel andsuccessively washed with aqueous, saturated NaHCO₃ solution (3×), H₂O,aqueous, saturated Cu₂SO₄, H₂O, and brine. The organic phase was passedthrough a Buchner funnel containing Na₂SO₄, and the filtrate wasevaporated to afford the carbamate product (Y) (24.84 g, 96% yield),which was used directly in the next step.

To a mixture of the carbamate (Y) (621 mg, 1.62 mmol) in dichloromethane(2 mL) was added triethylamine (227 μL, 1.63 mmol) and(S)-2-pyrrolidin-1-yl-methylpyrrolidine. After 1.5 hours, the reactionwas extracted into ethyl acetate and washed with aqueous, saturatedNaHCO₃ solution (3×), H₂O, and brine. The organic phase was passedthrough a Buchner funnel containing MgSO₄, and the filtrate wasevaporated to afford a residue that was dissolved in CHCl₃ and treatedwith macroporous-carbamate resin (to remove residual p-nitrophenol).After gentle agitation overnight, the mixture was filtered and thefiltrate evaporated to give the title compound (Z).

Preparation 2. 1-(1-Bromoethyl)-2,4,5-trifluorobenzene

Phosphorus tribromide (0.275 mL) and anhydrous methylene chloride (12mL) were combined and the solution cooled over ice water for 15 minutes.The solution was added to a mixture of 1-(2,4,5-trifluorophenyl)ethanol(0.506 g) and methylene chloride (8 mL), and the reaction was stirred atroom temperature for 1.5 hours. The reaction mixture was then pouredinto H₂O and extracted into methylene chloride. The organic phase wasisolated, dried with magnesium sulfate, filtered and concentrated(without heat) to give the title compound. ¹H-NMR (CD₃OD, 400 MHz) δ2.00 (3H, d, J=7.1 Hz), 5.37 (1H, m), 6.92 (1H, m), 7.36 (1H, m).

Preparation 3. 2-(1-Bromoethyl)-3-chloro-1,4-difluorobenzene

Phosphorus tribromide (1.3 mL) and anhydrous CH₂Cl₂ (50 mL) werecombined and then cooled over ice water for 20 minutes. The cooledsolution was then added to a mixture of1-(2-chloro-3,6-difluorophenyl)ethanol (2.71 g) and methylene chloride(50 mL), and the resulting mixture was stirred at room temperature fortwo (2) hours. The mixture was then poured into H₂O and extracted intoCH₂Cl₂. The organic phase was isolated, dried with magnesium sulfate,filtered, and concentrated to give the title compound (78% yield).

Example 1 (5-Iodo-3-nitro-pyridin-2-ylamino)-acetic acid ethyl ester

2-Chloro-5-iodo-3-nitro-pyridine (13 g) was dissolved in ethanol.Glycine ethyl ester HCl was added (5.0 eq) followed by triethylamine(5.0 eq). The reaction mixture was heated to 80° C. for four (4) hours.The reaction mixture was concentrated to dryness and triturated with H₂Oto give the title compound as a white solid (82-94% yield). M.p. 200° C.(dec), LCMS: m/z=352.08 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.30 (t, J=7.1Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.33 (d, J=5.6 Hz, 2H), 8.44 (bs, 1H),8.52 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H).

Example 2 7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

(5-Iodo-3-nitro-pyridin-2-ylamino)-acetic acid ethyl ester (17 g) wasdissolved in ethanol. SnCl₂2H₂O was added and the reaction mixture washeated to 80° C. for two (2) hours. The resulting precipitate wasfiltered and washed with ethanol to give the title compound as a rustcolored solid (59-77% yield). M.p. 81° C., LCMS: m/z=275.91 (M+H⁺),¹H-NMR (DMSO-d₆, 400 MHz) δ 3.94 (s, 2H), 6.94 (bs, 1H), 7.12 (d, J=1.8Hz, 1H), 7.74 (s, J=1.8 Hz, 1H), 10.40 (bs, 1H).

Example 31-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (300 mg) was reactedwith 2-chloro-3,6-difluorobenzyl bromide as in General Procedure 1. Thetitle compound was obtained as an off white solid (63% yield). M.p. 237°C., LCMS: m/z=436.17 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.01 (s, 2H),5.24 (s, 2H), 7.05 (d, J=1.5 Hz, 1H), 7.23-7.32 (m, 1H), 7.41-7.48 (m,1H), 7.79 (d, J=1.5 Hz, 1H).

Example 41-(2-Chloro-3,6-difluorobenzyl)-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(21 mg) was reacted with pyridine 3-boronic acid as in General Procedure4A, with the modification that the mixture was heated to 130° C. in amicrowave oven for 10 minutes. The reaction mixture was purified viareversed phase preparative HPLC to give the title compound as a paleyellow foam (48% yield). M.p. (foam), LCMS: m/z=387.24 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 4.53 (s, 2H), 5.51 (s, 2H), 7.13-7.19 (m, 2H), 7.34(s, 1H), 7.73 (s, 2H), 7.98-8.02 (m, 1H), 8.70-8.79 (m, 2H), 10.9 (bs,1H).

Example 54-[1-(2-Chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(280 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as inGeneral Procedure 4A, with the modification that the mixture was heatedto 130° C. in a microwave oven for 5 minutes. The title compound wasobtained as a white solid after silica gel chromatography (19% yield).M.p. 180-182° C., LCMS: m/z=458.37 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ1.34 (t, J=7.1 Hz, 3H), 4.08 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 5.39 (s,2H), 7.18 (bs, 1H), 7.29-7.33 (m, 1H), 7.39-7.47 (m, 1H), 7.42 (s, 1H),7.46 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.97 (s, 1H).

Example 64-[1-(2-Chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid

4-[1-(2-Chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester (43 mg) was saponified as described in GeneralProcedure 7 to give the title compound as a white solid (52% yield).M.p.>300° C., LCMS: m/z=430.31 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.15(s, 2H), 5.41 (s, 2H), 7.28-7.33 (m, 1H), 7.41-7.46 (m, 1H), 7.59 (s,1H), 7.67 (d, J=8.3 Hz, 2H), 7.98 (d, J=8.3 Hz, 2H), 8.09 (s, 1H).

Example 71-(2-Chloro-3,6-difluorobenzyl)-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

4-[1-(2-Chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (13 mg) was reacted with 1-methyl piperazine as in GeneralProcedure 8 to give the title compound as an off-white foam (45% yield).M.p. (foam), LCMS: m/z=512.07 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ2.30-2.43 (m, 2H), 2.83 (s, 3H), 3.06-3.18 (m, 2H), 3.21-3.33 (m, 2H),3.40-3.48 (m, 2H), 4.08 (s, 2H), 5.39 (s, 2H), 7.28 (bs, 1H), 7.22-7.32(m, 1H), 7.46 (s, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H),8.05 (s, 1H).

Example 8 1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.623 g) was reactedwith benzyl bromide as in General Procedure 1 to give the title compoundas a light yellow solid (38% yield). M.p. 225° C., LCMS: m/z=366.03(M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.14 (s, 2H), 5.10 (s, 2H), 7.13 (s,1H), 7.7.22-7.29 (m, 4H), 7.31-7.38 (m, 2H), 7.78 (s, 1H).

Example 94-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid ethyl ester

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (509 mg) wasreacted with 4-ethoxycarbonyl phenyl boronic acid as in GeneralProcedure 4B to give the title compound as a brown solid (72% yield).M.p.=178° C., LCMS: m/z=388.23 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.32(3H, t, J=7.1 Hz), 4.20 (2H, d, J=1.5 Hz), 4.31 (2H, q, J=7.1 Hz), 5.26(2H, s), 7.23 (2H, m), 7.32 (2H, s), 7.34 (2H, m), 7.39 (1H, d, J=1.8Hz), 7.63 (2H, d, J=8.6 Hz), 7.94 (2H, d, J=8.3 Hz), 8.06 (1H, d, J=2.0Hz).

Example 104-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid ethyl ester (390 mg) was saponified under the conditions of GeneralProcedure 7 to give the title compound as a light brown solid (99%yield). M.p.>200° C., LCMS: m/z=360.17 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz)δ 4.19 (2H, s), 5.26 (2H, s), 7.23 (2H, s), 7.32 (4H, m), 7.39 (1H, s),7.60 (2H, d, J=8.3 Hz), 7.92 (2H, d, J=8.3 Hz), 8.05 (1H, s).

Example 111-Benzyl-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (100 mg) wasreacted with 3-pyridine boronic acid as in General Procedure 4A to givethe title compound as a light yellow solid (60% yield). M.p. 58° C.,LCMS: m/z=317.16 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 4.42 (s, 2H),7.22-7.31 (m, 2H), 7.32-7.38 (m, 4H), 7.50 (s, 1H), 7.85-7.92 (m, 1H),8.02 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.65-8.75 (m, 1H), 8.75-8.90 (m,1H).

Example 124-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)benzamide,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (23 mg) was coupled to 2-pyrrolidin-1-yl-ethylamine as in GeneralProcedure 8 to give the title compound as a brown solid afterpreparative reversed-phase HPLC purification (29% yield). M.p.=107° C.,LCMS: m/z=456.15 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.13 (4H, m), 3.40(6H, m), 3.81 (4H, m), 4.54 (2H, s), 5.27 (2H, s), 7.38 (4H, m), 7.75(1H, s), 7.92 (2H, d, J=8.3 Hz).

Example 13S-1-Benzyl-7-[4-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (48 mg) was coupled to (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidineas in General Procedure 8 to give the title compound as a pink solidafter preparative reversed-phase HPLC purification (43% yield). LCMS:m/z=496.24 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.94 (3H, m), 2.13 (4H,bs), 2.29 (1H, m), 3.05 (1H, bs), 3.24 (2H, m), 3.38 (1H, m), 3.49 (1H,m), 3.64 (3H, m), 3.86 (1H, bs), 4.05 (1H, bs), 4.57 (3H, s), 5.29 (2H,s), 7.35 (8H, m), 7.61 (2H, d, J=8.1 Hz), 7.74 (1H, s).

Example 144-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-morpholin-4-yl-propyl)benzamide,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (43 mg) was coupled to 3-morpholin-4-yl-propylamine as in GeneralProcedure 8 to give the title compound as an orange solid afterpreparative reversed-phase HPLC purification (12% yield). LCMS:m/z=486.24 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.13 (3H, m), 3.18 (4H, m),3.40 (1H, m), 3.53 (5H, m), 4.00 (6H, m), 4.57 (2H, s), 5.28 (2H, s),7.36 (8H, m), 7.71 (1H, s), 7.93 (2H, d, J=8.3 Hz)

Example 154-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(4-dimethylaminobutyl)benzamide,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (40 mg) was coupled to 3-dimethylaminobutylamine as in GeneralProcedure 8 to give the title compound as a yellow solid afterpreparative reversed-phase HPLC purification (17% yield). LCMS:m/z=458.19 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.70 (2H, m), 1.79 (2H, m),2.89 (6H, s), 3.19 (2H, t, J=8.0 Hz), 3.45 (2H, t, J=6.7 Hz), 4.50 (2H,s), 5.36 (2H, s), 7.30 (1H, m), 7.37 (4H, m), 7.49 (2H, d, J=8.3 Hz),7.54 (1H, d, J=1.5 Hz), 7.88 (3H, m).

Example 164-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(6-dimethylaminohexyl)benzamide

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (47 mg) was coupled to 3-dimethylaminohexylamine as in GeneralProcedure 8 to give the title compound as a light brown solid (19%yield). M.p.>200° C., LCMS: m/z=486.19 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ2.28 (9H, m), 3.47 (3H, m), 4.35 (2H, s), 4.96 (1H, bs), 5.21 (2H, s),7.20 (2H, m), 7.35 (5H, m), 7.52 (1H, s), 7.77 (2H, d, J=8.3 Hz), 7.99(1H, d, J=2.0 Hz).

Example 171-Benzyl-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (22 mg) was coupled to 4-(1 pyrrolidinyl)piperidine as in GeneralProcedure 8 to give the title compound as a tan solid after preparativereversed-phase HPLC purification (16% yield). LCMS: m/z=494.27 (M+H⁺),¹H-NMR (CD₃OD, 400 MHz) δ 1.67 (2H, bs), 2.10 (8H, m), 3.19 (3H, m),3.45 (1H, m), 3.67 (2H, bs), 3.91 (1H, bs), 5.57 (2H, s), 7.28 (1H, m),7.36 (4H, m), 7.51 (2H, d, J=8.1 Hz), 7.61 (2H, d, J=8.1 Hz), 7.78 (1H,d, J=1.5 Hz), 8.44 (1H, d, J=1.0 Hz).

Example 18S-1-Benzyl-7-[3-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (33 mg) was coupled to (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidineas in General Procedure 8 to give the title compound as a yellow solidafter preparative reversed-phase HPLC purification (32% yield). LCMS:m/z=496.24 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.85 (2H, m), 2.00 (1H, m),2.09 (2H, m), 2.23 (2H, m), 2.37 (1H, m), 3.21 (3H, m), 3.57 (5H, m),3.76 (1H, m), 4.08 (1H, m), 4.38 (2H, s), 4.59 (1H, m), 5.34 (2H, s),7.30 (1H, m), 7.38 (4H, m), 7.42 (1H, d, J=1.5 Hz), 7.55 (3H, s), 7.60(1H, s), 7.92 (1H, s), 8.09 (1H, s).

Example 193-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino-ethyl)benzamide,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (33 mg) was coupled to 3-dimethylaminoethylamine as in GeneralProcedure 8 to give the title compound as a yellow solid afterpreparative reversed-phase HPLC purification (34% yield). LCMS:m/z=430.22 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.92 (6H, s), 3.67 (3H, m),3.82 (2H, t, J=5.6 Hz), 4.00 (1H, s), 4.55 (2H, s), 5.30 (2H, s), 7.34(7H, m), 7.49 (2H, m), 7.73 (1H, s), 7.87 (2H, m).

Example 201-Benzyl-7-[3-(pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (31 mg) was coupled to pyrrolidine as in General Procedure 8 togive the title compound as a yellow solid (47% yield). LCMS: m/z=413.30(M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.92 (2H, m), 2.02 (2H, m), 3.36 (1H,m), 3.40 (2H, t, J=6.6 Hz), 3.62 (2H, t, J=6.9 Hz), 4.49 (2H, s), 4.91(1H, s), 5.36 (2H, s), 7.29 (1H, m), 7.37 (2H, d, J=1.8 Hz), 7.39 (2H,s), 7.49 (1H, s), 7.52 (3H, s), 7.53 (1H, d, J=1.5 Hz), 7.84 (1H, d,J=1.5 Hz).

Example 217-(4-Acetylphenyl)-1-benzyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (35 mg) wasreacted with 4-acetylphenyl boronic acid as in General Procedure 4B togive the title compound as a yellow solid (20% yield). M.p.=200° C.,LCMS: m/z=358.24 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.61 (3H, s), 4.36(2H, s), 5.22 (2H, s), 7.21 (1H, d, J=2.0 Hz), 7.28 (4H, m), 7.37 (4H,m), 7.96 (2H, d, J=8.3 Hz), 8.01 (1H, d, J=1.8 Hz).

Example 223-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide

3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (35 mg) was coupled with ethylamine as in General Procedure 8 togive the title compound as a yellow solid (3% yield). LCMS: m/z=387.26(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.27 (3H, t, J=7.2 Hz), 3.47 (2H,quartet, J=7.2 Hz), 4.50 (2H, s), 5.28 (2H, s), 7.36 (8H, m), 7.48 (1H,t, J=7.6 Hz), 7.79 (2H, m), 7.84 (1H, s).

Example 234-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzamide

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg) wasreacted with 4-carbamoylphenyl boronic acid as in General Procedure 4Bto give the title compound as a white solid (24% yield). M.p.>200° C.,LCMS: m/z=359.22 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.22 (2H, s), 5.28(2H, s), 7.24 (1H, m), 7.33 (5H, m), 7.41 (1H, s), 7.56 (2H, d, J=8.6Hz), 7.88 (2H, d, J=8.3 Hz), 7.96 (1H, bs), 8.04 (1H, d, J=1.8 Hz).

Example 241-Benzyl-7-(4-methanesulfonyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (46 mg) wasreacted with 4-(methanesulfonyl)phenyl boronic acid as in GeneralProcedure 4B to give the title compound as a yellow solid (43% yield).LCMS: m/z=394.22 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.08 (3H, s), 4.54(2H, s), 5.28 (2H, s), 7.30 (3H, m), 7.39 (3H, m), 7.45 (2H, d, J=8.3Hz), 7.78 (1H, d, J=1.5 Hz), 7.94 (2H, d, J=8.3 Hz).

Example 251-Benzyl-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (43 mg) wasreacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a white solidafter preparative reversed-phase HPLC purification (38% yield). LCMS:m/z=442.23 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 2.95 (3H, s), 3.19 (3H, m),3.31 (4H, m), 3.48 (2H, m), 4.52 (2H, s), 5.36 (2H, s), 7.29 (1H, m),7.37 (4H, m), 7.53 (5H, m), 7.85 (1H, d, J=1.8 Hz).

Example 261-Benzyl-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (45 mg) was coupled with 4-(1 pyrrolidinyl)piperidine as in GeneralProcedure 8 to give the title compound as a yellow solid afterpreparative reversed-phase HPLC purification (28% yield). LCMS:m/z=496.15 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.67 (2H, m), 2.09 (7H, m),3.17 (3H, m), 3.41 (2H, m), 3.66 (2H, m), 3.86 (2H, bs), 4.51 (2H, s),5.36 (2H, s), 7.29 (1H, m), 7.38 (4H, s), 7.50 (1H, d, J=1.5 Hz), 7.53(2H, m), 7.85 (1H, d, J=1.5 Hz).

Example 274-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide

4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid (43 mg) was coupled with ethylamine as in General Procedure 8 togive the title compound as a tan solid (15% yield). M.p.=195° C., LCMS:m/z=387.31 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.24 (3H, t, J=7.3 Hz),3.44 (2H, quartet, J=7.3 Hz), 4.51 (2H, s), 5.26 (2H, s), 7.33 (8H, m),7.76 (1H, d, J=8.6 Hz), 7.81 (2H, d, J=8.1 Hz), 8.05 (1H, d, J=8.3 Hz).

Example 285-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (196 mg) wasreacted with 2-cyanopyridine-5-boronic acid pinacol ester as in GeneralProcedure 4B to give the title compound as a yellow solid (46% yield).M.p.>200° C., LCMS: m/z=342.20 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.23(2H, s), 5.27 (2H, s), 7.23 (1H, m), 7.32 (4H, m), 7.49 (2H, m), 8.03(1H, d, J=8.3 Hz), 8.18 (2H, m), 8.95 (1H, d, J=2.0 Hz).

Example 295-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carboxylicacid ethyl ester

5-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile(32 mg) was mixed with ethanol (1.5 mL) and 4 N HCl (2.0 mL) in dioxaneand then heated in a microwave oven at 150° C. for 80 minutes. Thereaction mixture was concentrated and purified with preparativereversed-phase HPLC to give the title compound as an orange solid. LCMS:m/z=389.22 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.42 (3H, t, J=7.1 Hz),4.44 (4H, m), 5.35 (2H, s), 7.28 (1H, m), 7.37 (5H, m), 7.55 (1H, d,J=1.8 Hz), 8.00 (1H, d, J=1.8 Hz), 8.03 (1H, dd, J=8.1, 2.3 Hz), 8.17(1H, d, J=8.3 Hz), 8.69 (1H, d, J=2.0 Hz).

Example 303-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid methyl ester

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (370 mg) wasreacted with 3-methoxycarbonyl phenyl boronic acid as in GeneralProcedure 4A to give the title compound as a white solid (70% yield).M.p. 211° C., LCMS: m/z=374.17 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 3.95(s, 3H), 4.48 (s, 2H), 5.35 (s, 2H), 7.23-7.35 (m, 2H), 7.38-7.40 (m,2H), 7.50-7.58 (m, 2H), 7.60-7.66 (m, 2H), 7.84 (s, 1H), 7.9-8.1 (m,2H).

Example 313-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid

3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid methyl ester (245 mg) was saponified as in General Procedure 7 togive the title compound as a tan film (73% yield). M.p. (film), LCMS:m/z=360.18 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 4.53 (s, 2H), 5.37 (s, 2H),7.28-7.35 (m, 1H), 7.37-7.45 (m, 4H), 7.52-7.58 (m, 1H), 7.62-7.65 (m,2H), 7.82 (d, J=1.8 Hz, 1H), 8.03 (s, 1H), 8.04 (d, J=8.8 Hz, 1H).

Example 32 1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg) wasdissolved in anhydrous tetrahydrofuran and added to LiAlH₄ (1 M intetrahydrofuran, 9.0 eq) over 2 minutes. After stirring for 35 minutesat room temperature, the reaction mixture was quenched with wet ether,diluted with ethyl acetate and H₂O, and filtered. The organic phase wasisolated, dried, filtered, and concentrated. Silica gel chromatography(0-10% methanol in CH₂Cl₂) gave the title compound as a pale yellow film(10% yield). M.p. (film), LCMS: m/z=226.19 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 3.35-3.40 (m, 2H), 3.52-3.57 (m, 2H), 4.40 (s, 2H), 4.83 (bs,1H), 6.41-6.50 (m, 1H), 6.56-6.63 (m, 1H), 7.20-7.38 (m, 5H), 7.43 (d,J=1.2H).

Example 33 1-Benzyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg) wasreduced as in General Procedure 3 to give the title compound as a lightbrown solid (25% yield). M.p. 147-148° C., LCMS: m/z=352.02 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 3.09-3.32 (m, 2H), 3.51-3.54 (m, 2H), 4.36 (s,2H), 6.84 (s, 1H), 7.23-7.30 (m, 1H), 7.31-7.39 (m, 4H), 7.58 (d, J=1.5Hz, 1H).

Example 341-Benzyl-7-pyridin-3-yl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-Benzyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (30 mg) wasreacted with pyridine 3-boronic acid as in General Procedure 4A to givethe title compound as a light yellow film (23% yield). M.p. (film),LCMS: m/z=303.40 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.41-3.44 m, 2H),3.60-3.63 (m, 2H), 4.49 (s, 2H), 6.80 (s, 1H), 5.40 (bs, 1H), 6.80 (s,1H), 7.27-7.42 (m, 5H), 7.64 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 8.48 (d,J=4.8 Hz, 1H), 8.63 (s, 1H).

Example 354-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acidethyl ester

(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (293mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in GeneralProcedure 4A to give the title compound as a pale yellow solid (42%yield). M.p. 178-179° C., LCMS: m/z=374.30 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.38 (t, J=7.1) Hz, 3H), 3.40 (t, J=5.1 Hz, 2H), 3.60-3.63 (m,2H), 4.35 (q, J=7.1 Hz, 2H), 4.48 (s, 2H), 6.85 (s, 1H), 7.27-7.49 (m,5H), 7.43 (d, J=8.3 Hz, 2H), 7.73 (d, J=2.0 Hz, 2H), 8.00 (d, J=8.3 Hz,2H).

Example 364-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid

4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acidethyl ester (118 mg) was saponified as in General Procedure 7 to givethe title compound as a pale yellow solid (90% yield). M.p.>300° C.,LCMS: m/z=346.30 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.35-3.38 (m, 2H),3.52-3.54 (m, 2H), 4.62 (s, 2H), 7.08 (s, 1H), 7.25-7.27 (m, 1H),7.29-7.32 (m, 4H), 7.62 (d, J=8.4 Hz, 2H), 7.69 (d, J=1.8 Hz, 1H), 7.92(d, J=8.4 Hz, 2H), 12.86 (bs, 1H).

Example 37[4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-methylpiperazin-1-yl)methanone

4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20mg) was reacted with 1-methyl piperazine as in General Procedure 8 togive the title compound as a yellow solid (32% yield). M.p. 180-181° C.,LCMS: m/z=428.30 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.31 (s, 3H),2.33-2.52 (m, 4H), 3.38-3.43 (m, 2H), 3.45-3.55 (m, 2H), 3.46-3.50 (m,2H), 3.58-3.62 (m, 2H), 3.64-3.82 (m, 2H), 4.48 (s, 2H), 5.29 (s, 1H),6.83 (s, 1H), 7.27-7.39 (m, 9H), 7.69 (s, 1H).

Example 38[4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-((S)-2-pyrrolidinylmethylpyrrolidin-1-yl)methanone,trifluoroacetic acid salt

4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20mg) was reacted with (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine as inGeneral Procedure 8 to give the title compound as a yellow foam afterreversed phase preparative HPLC (43% yield). M.p. foam, LCMS: m/z482.30, ¹H-NMR (CDCl₃, 400 MHz) δ 1.82-1.84 (m, 1H), 1.92-2.05 (m, 2H),2.06-2.20 (m, 4H), 2.92-3.08 (m, 1H), 3.18-3.25 (m, 1H), 3.25-3.35 (m,1H), 3.39-48 (m, 2H), 3.50-3.5 (m, 1H), 3.55-3.63 (m, 1H), 3.65-3.71 (m,1H), 3.72-3.77 (m, 2H), 3.82-3.94 (m, 1H), 4.01-4.11 (m, 1H), 4.48-4.59(m, 3H), 6.92 (s, 1H), 7.26-7.42 (m, 8H), 7.56 (d, J=8.1 Hz, 2H), 11.06(bs, 1H).

Example 39[4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20mg) was reacted with 4-(1 pyrrolidinyl)piperidine as in GeneralProcedure 8 to give the title compound as a yellow solid (22% yield).M.p. 120° C., LCMS: m/z=482.26 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.53-1.65 (m, 7H), 1.90-2.04 (m, 3H), 2.25-2.35 (m, 1H), 2.53-2.63 (m,4H), 2.91-3.06 (m, 2H), 3.38-3.44 (m, 2H), 3.59-3.62 (m, 2H), 4.48 (s,2H), 5.01 (bs, 1H), 6.84 (s, 1H), 7.28-7.40 (m, 9H), 7.70 (s, 1H).

Example 40 7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (200 mg) was reduced asin General Procedure 3 using 4 eq DIBAL-H to give the title compound asa white solid (31% yield). M.p. 126-128° C., LCMS: m/z=262.30 (M+H⁺),¹H-NMR (DMSO-d₆, 400 MHz) δ 3.13-3.17 (m, 2H), 3.27-3.29 (m, 2H), 5.78(s, 1H), 6.37 (s, 1H), 6.78 (d, J=2.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H).

Example 41 (3,4-Dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone

1,2,3,4-tetrahydropyrido[2,3-b]pyrazine was reacted with benzoylchloride as in General Procedure 2 to give the title compound as a beigesolid (<10% yield). M.p. 166-168° C., LCMS: m/z=240.12 (M+H⁺), ¹H-NMR(DMSO-d₆, 400 MHz) δ 3.45-3.49 (m, 2H), 3.84-3.87 (m, 2H), 6.40 (s, 1H),6.77 (dd, J=4.8 Hz, 4.5 Hz, 1H), 6.92 (dd, J=1.5 Hz, 7.8 Hz, 1H), 7.10(dd, J=1.5 Hz, 4.6 Hz, 1H), 7.25-7.34 (m, 5H).

Example 42(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted withbenzoyl chloride as in General Procedure 2 to give the title compound asa pale yellow solid (61% yield). M.p. 164-166° C., LCMS: m/z=366.00(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.45-3.50 (m, 2H), 3.90 (t, J=4.8 Hz,2H), 7.37-7.47 (m, 6H), 7.95 (s, 1H).

Example 43Phenyl-(7-pyridin-3-yl-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone

(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone (50 mg)was reacted with pyridine 3-boronic acid as in General Procedure 4A togive the title compound as a yellow solid (25% yield). M.p. 219-220° C.,LCMS: m/z=317.40 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.45-3.50 (m, 2H),4.02 (t, J=4.8 Hz, 2H), 5.39 (s, 1H), 7.20-7.22 (m, 2H), 7.40-7.44 (m,3H), 7.47-7.51 (m, 3H), 8.03 (s, 1H), 8.30 (s, 1H), 8.47 (d, J=4.3 Hz,1H).

Example 444-(1-Benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acidethyl ester

(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone (215mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in GeneralProcedure 4A to give the title compound as an off-white solid (32%yield). M.p. 177-178° C., LCMS: m/z=388.23 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.38 t, (J=7.1 Hz, 3H), 3.67-3.72 (m, 2H), 4.01-4.08 (m, 2H),4.36 (q, J=7.1 Hz, 2H), 5.21 (bs, 1H), 7.12-7.16 (m, 2H), 7.40-7.53 (m,5H), 7.95 (d, J=8.3 Hz, 2H), 8.08 (s, 1H).

Example 45 2-Pyrrolidin-1-yl-ethanesulfonicacid[4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide,trifluoroacetic acid salt

2-pyrrolidin-1-yl-ethanesulfonicacid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide wasprepared as in General Procedure 11 and then reacted with1-benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (31 mg) as inGeneral Procedure 4B to give the title compound as a yellow solid afterpurification by preparative reversed-phase HPLC (38% yield). LCMS:m/z=492.09 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 2.08 (4H, bs), 3.13 (2H,m), 3.63 (6H, m), 4.51 (2H, s), 5.34 (2H, s), 7.30 (3H, m), 7.37 (6H,m), 7.51 (1H, s), 7.75 (1H, s).

Example 46 2-Pyrrolidin-1-yl-ethanesulfonicacid[4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide

2-Pyrrolidin-1-yl-ethanesulfonicacid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide (50mg) was prepared as in General Procedure 11 and then reacted with(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone as inGeneral Procedure 4A to give the title compound as an off-white foam(18% yield). M.p. foam, LCMS: m/z=492.10 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz)δ 1.33 (s, 1H), 1.76-1.82 (m, 4H), 2.45-2.55 (m, 4H), 3.02 (t, J=6.3 Hz,2H), 3.22 (t, J=6.0 Hz, 2H), 3.63-3.68 (m, 2H), 4.02 (t, J=4.6 Hz, 2H),5.33 (bs, 1H), 6.98-7.-4 (m, 2H), 7.11 (d, J=8.3 Hz, 2H), 7.26 (s, 1H),7.47 (d, J=8.3 Hz, 2H), 7.48-7.54 (m, 3H), 7.98 (d, J=2.0 Hz, 1H).

Example 47 2-(4-Methylpiperazin-1-yl)-ethanesulfonicacid[4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide

2-(4-Methylpiperazin-1-yl)-ethanesulfonicacid[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]amide (50 mg)was prepared as in General Procedure 11 and then reacted with(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone as inGeneral Procedure 4A to give the title compound as a yellow foam (45%yield). M.p. foam, LCMS: m/z=521.20 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.68 (s, 3H), 2.35-2.58 (m, 8H), 2.90 (t, J=6.6 Hz, 2H), 3.23 (t, J=6.3Hz, 2H), 3.65-3.69 (m, 2H), 3.97-4.05 (m, 2H), 5.45 (bs, 1H), 6.99-7.06(m, 2H), 7.16 (d, J=8.3 Hz, 2H), 7.27 (s, 1H), 7.39-7.53 (m, 5H), 7.99(d, J=1.8 Hz, 1H).

Example 48 2-Pyrrolidin-1-yl-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide

2-Pyrrolidin-1-yl-ethanesulfonicacid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide (40mg) was prepared as in General Procedure 11 and then reacted with1-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-oneas in General Procedure 4A with the modification that the reaction washeated to 130° C. in a microwave oven for 10 minutes. The title compoundwas isolated as an off-white solid (36% yield). M.p.>300° C., LCMS:m/z=528.03 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.83-1.86 (m, 4H),2.52-2.64 (m, 4H), 3.06 (t, J=6.3 Hz, 2H), 3.25 (t, J=6.3 Hz, 2H), 4.32(s, 2H), 4.97 (bs, 1H), 5.21 (s, 2H), 6.89-6.98 (m, 2H), 7.05-7.11 (m,1H), 7.16 (d, J=1.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.26 (s, 1H), 7.33(d, J=8.6 Hz, 2H), 7.92 (s, 1H).

Example 492-[Ethyl-((S)-1-pyrrolidin-1-ylmethyl-propyl)-amino]-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide

2-[Ethyl-((S)-1-pyrrolidin-1-ylmethyl-propyl)-amino]-ethanesulfonicacid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide (40mg) was prepared as in General Procedure 11 and then reacted with1-(2,5-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-oneas in General Procedure 4A with the modification that the reaction washeated to 130° C. in a microwave oven for 10 minutes. The title compoundwas obtained as a light yellow foam (10% yield). M.p. foam, LCMS:m/z=611.07 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.44-1.53 (m, 1H),1.82-1.99 (m, 5H), 2.22-2.25 (m, 1H), 2.26-2.33 (m, 2H), 2.45-2.55 (m,2H), 2.70-2.92 (m, 7H), 2.90-3.12 (m, 2H), 3.44-3.60 (m, 2H), 4.32 (s,2H), 4.96 (s, 1H), 5.21 (s, 2H), 6.88-6.98 (m, 2H), 7.04-7.12 (m, 1H),7.18 (s, 1H), 7.29 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 7.98 (d,J=1.89 Hz, 1H).

Example 50 2-Morpholin-4-yl-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide

2-Morpholin-4-yl-ethanesulfonicacid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide (40mg) was prepared as in General Procedure 11 and then reacted with1-(2,5-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-oneas in General Procedure 4A to give the title compound as a white solid(11% yield). m.p. 225° C., LCMS: in/Z=544.20 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.51 (t, J=4.5 Hz, 4H), 2.92 (t, J=6.3 Hz, 2H), 3.28 (t, J=6.3Hz, 2H), 4.31 (s, 2H), 4.95 (s, 1H), 5.22 (s, 2H), 6.91-6.99 (m, 2H),7.05-7.10 (m, 1H), 7.14 (s, 1H), 7.25 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.6Hz, 2H), 7.92 (s, 1H).

Example 51 2-Pyrrolidin-1-yl-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide

2-Pyrrolidin-1-yl-ethanesulfonicacid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide (39mg) was prepared as in General Procedure 11 and then reacted with1-(2,5-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine asin General Procedure 4A with the modification that the reaction washeated to 130° C. in a microwave oven for 10 minutes. The title compoundwas obtained as a light yellow solid (15% yield). M.p. slow decomp,LCMS: m/z=(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.80-1.84 (m, 4H), 2.54-2.58(m, 4H), 3.03 (t, J=6.1 Hz, 2H), 3.23 (t, J=6.1 Hz, 2H), 3.45 (t, J=5.3Hz, 2H), 3.60-3.64 (m, 2H), 4.49 (s, 2H), 5.03 (bs, 1H), 6.73 (s, 1H),6.92-7.08 (m, 3H), 7.17 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.66(d, J=1.8 Hz, 1H), 8.08 (s, 1H).

Example 524-(1-Benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino-ethyl)benzamide

(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (50mg) was reacted withN-(2-dimethylaminoethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamideas in General Procedure 4A to give the title compound as a light yellowsolid (24% yield). M.p. 145-147° C., LCMS: m/z=430.26 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 2.28 (s, 6H), 2.48-2.53 (m, 2H), 3.48-3.54 (m, 2H),3.66-3.71 (m, 2H0, 4.01 (t, J=4.8 Hz, 2H), 5.55 (bs, 1H), 6.84-6.87 (m,1H), 7.09-7.15 (m, 2H), 7.38-7.52 (m, 6H), 7.71 (d, J=8.1 Hz, 2H), 8.05(d, J=2.0 Hz, 1H).

Example 534-(1-Benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-dimethylamino-propyl)benzamide

(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (50mg) was reacted withN-(3-dimethylamino-propyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamideas in General Procedure 4A to give the title compound as a light yellowsolid (44% yield). M.p. 94° C., LCMS: m/z=444.20 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 1.72-1.80 (m, 2H), 2.27 (s, 6H), 2.48-2.53 (t, J=5.8 Hz, 2H),3.48-3.54 (m, 2H), 3.67-3.73 (m, 2h), 3.98-4.04 (m, 2H), 5.44 (bs, 1H),7.10-7.18 (m, 2H), 7.36-7.48 (m, 6H), 7.69 (d, J=8.1 Hz, 2H), 8.07 (s,1H), 8.42 (bs, 1H).

Example 54{7-[4-(4-Methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}phenylmethanone

(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (50mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]doxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a light greenfoam (53% yield). M.p. foam, LCMS: m/z=442.30 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.32 (s, 3H), 2.35-2.48 (m, 4H), 3.40-3.50 (m, 2H), 3.62-3.69 (M,2h), 3.70-3.80 (m, 2h), 3.97-4.03 (m, 2H), 5.42 (bs, 1H), 7.06-7.15 (m,2H), 7.34 (d, J=8.1 Hz, 2H), 7.40-7.52 (m, 6H), 8.05 (s, 1H).

Example 554-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester

1-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(600 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as inGeneral Procedure 4A to give the title compound as an off-white solid(62% yield). M.p. 201-203° C., LCMS: m/z=424.20 (M+H⁺), ¹H-NMR (DMSO-d₆,400 MHz) δ 1.32 (t, J=7.0 Hz, 3H), 3.99 (s, 2H), 4.32 (q, J=7.0 Hz, 2H),5.26 (s, 2H), 7.03-7.09 (m, 1H), 7.11-7.19 (m, 1H), 7.33 (s, 1H),7.34-7.38 (m, 1H), 7.39 (s, 1H), 7.67 (d, J=7.0 Hz, 2H), 6.8 Hz, 2H),8.10 (s, 1H).

Example 564-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid

4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester (385 mg) was saponified as in General Procedure 7 togive the title compound as an off-white solid (85% yield). M.p.>300° C.,LCMS: m/z=396.13 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.21 (s, 2H), 5.26(s, 2H), 7.05-7.11 (m, 1H), 7.12-7.18 (m, 1H), 7.27-7.38 (m, 1H), 7.66(d, J=7.3 Hz, 2H), 7.94 (d, J=7.1 Hz, 2H), 8.10 (s, 1H).

Example 571-(2,5-Difluorobenzyl)-7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (35 mg) was reacted with(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 togive the title compound as a white solid (32% yield). M.p. 125° C.,LCMS: m/z=532.10 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.22-1.26 (m, 2H),1.68-1.82 (m, 4H), 1.89-2.15 (m, 4H), 2.56-2.70 (m, 3H), 2.80-2.90 (m,1H), 3.42-3.52 (m, 1H), 4.33 (s, 2H), 4.43-4.50 (m, 1H), 5.02 (bs, 1H),5.22 (s, 2H), 6.91-6.98 (m, 2H), 7.04-7.10 (m, 1H), 7.21 (d, J=1.5 Hz,1H), 7.39 (d, J=8.1 Hz, 2H), 7.54 (bd, J=7.6 Hz, 2H), 8.01 (d, J=1.5 Hz,2H).

Example 584-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin-1-yl-ethyl)benzamide

4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (35 mg) was reacted with N-(2-aminoethyl)pyrrolidine as in GeneralProcedure 8 to give the title compound as a white solid (25% yield).M.p. 235° C. (dec), LCMS: m/z=492.20 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.81-18.5 (m, 4H), 2.55-2.65 (m, 4H), 2.72-2.80 (m, 2H), 3.58-3.62 (m,2H), 4.68 (s, 2H), 4.99 (s, 1H), 5.23 (s, 2H), 6.85-6.95 (m, 2H),7.02-7.08 (m, 1H), 7.07 (s, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.1Hz, 2H), 8.03 (s, 1H), 8.08 (s, 1H).

Example 591-(2,5-Difluorobenzyl)-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (35 mg) was reacted with 1-methyl piperazine as in GeneralProcedure 8 to give the title compound as a light yellow solid (38%yield). m.p. 223° C. (dec), LCMS: m/z=478.20 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.32 (s, 3H), 2.35-2.48 (m, 4H), 3.48-3.54 (m, 2H), 3.70-3.80 (m,2H), 4.34 (s, 2H), 5.11 (s, 1H), 5.22 (s, 2H), 6.90-6.98 (m, 2H),7.06-7.13 (m, 1H), 7.20 (d, J=1.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.45(d, J=8.3 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H).

Example 601-(2,5-Difluorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (35 mg) was reacted with 4-(1 pyrrolidinyl)piperidine as in GeneralProcedure 8 to give the title compound as a pale yellow solid (30%yield). M.p. 186° C. (dec) m/z=532.30 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.44-1.58 (m, 4H), 1.90-2.06 (m, 2H), 2.28-2.32 (m, 1H), 2.52-2.64 (m,4H), 2.85-3.11 (m, 3H), 3.70-3.82 (m, 2H), 4.34 (s, 2H), 4.50-4.62 (m,2H), 5.06 (s, 1H), 5.22 (s, 2H), 6.6.88-6.96 (m, 2H), 7.10-7.22 (m, 1H),7.20 (s, 1H), 7.40 (dd, J=8.3 Hz, 2H), 8.01 (s, 1H).

Example 61 (S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide

1-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(35 mg) was reacted with the product of Preparation 1 (i.e.,(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amide(N)) as in General Procedure 4A to give the title compound as an orangefoam (29% yield). M.p. foam, LCMS: m/z=547.10 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.65-1.73 (m, 2H), 1.89-1.95 (m, 4H), 2.45-2.50 (m, 1H),2.55-2.68 (m, 2H), 2.79-2.89 (m, 2H), 2.91-2.99 (m, 1H), 3.30-3.38 (m,1H), 3.42-3.52 (m, 1H), 3.79-3.92 (m, 2H), 4.30 (s, 1H), 4.88 (bs, 1H),5.20 (s, 2H), 6.87-7.09 (m, 4H), 7.15 (s, 1H), 7.23-7.27 (m, 2H), 7.35(d, J=8.3 Hz, 2H), 7.98 (s, 1H).n 11.09 (bs, 1H).

Example 621-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (525 mg) was reactedwith 2,5-difluorobenzyl bromide as in General Procedure 1 to give1-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-oneas a tan solid (70% yield). This amide was then reduced as in GeneralProcedure 3 to give the title compound as a white solid (42% yield).M.p. 175° C., LCMS: m/z=388.10 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ3.26-3.30 (m, 2H), 3.36-3.42 (m, 2H), 4.44 (s, 2H), 6.63 (bs, 1H), 6.77(s, 1H), 7.05-7.10 (m, 1H), 7.15-7.19 (m, 1H), 7.20-7.27 (m, 1H), 7.41(s, 1H).

Example 634-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester

1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(500 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as inGeneral Procedure 4A to give the title compound as an off-white solid(63% yield). M.p. 173-174° C., LCMS: m/z=410.30 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 1.39 (t, J=7.1 Hz, 3H), 3.45 (t, J=5.0 Hz, 2H), 3.61-3.66 (m,2H), 4.37 (q, J=7.1 Hz, 2H), 4.49 (s, 2H), 5.32 (bs, 1H), 6.78 (d, J=1.5Hz, 1H), 6.89-6.96 (m, 1H), 6.99-7.08 (m, 2H), 7.45 (d, J=8.4 Hz, 2H),7.76 (d, J=1.8 Hz, 2H), 8.02 (d, J=8.6 Hz, 2H).

Example 644-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid

4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester (300 mg) was saponified as in General Procedure 7 togive the title compound as a beige solid (91% yield). M.p.>300° C.,LCMS: m/z=382.20 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.28-3.33 (m, 2H),3.40-3.49 (m, 2H), 4.58 (s, 2H), 6.58 (s, 1H), 6.77 (s, 1H), 7.10-7.20(m, 2H), 7.26-7.34 (m, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.73 (s, 1H), 7.89(d, J=8.3 Hz, 2H), 12.92 (bs, 1H).

Example 65{4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone

4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (50 mg) was reacted with(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 togive the title compound as a pale yellow solid (53% yield). M.p.143-144° C., LCMS: m/z=518.30 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.48-1.58 (m, 1H), 1.87-2.15 (m, 4H), 2.17-2.22 (m, 3H), 2.55-2.64 (m,4H), 2.83-2.89 (m, 1H), 3.12-3.23 (m, 1H), 3.42-3.50 (m, 2H), 3.60-3.64(m, 2H), 4.40-4.49 (m, 3H), 5.07 (bs, 1H), 6.76 (s, 1H), 6.86-7.09 (m,3H), 7.41 (d, J=8.1 Hz, 2H), 7.45-7.52 (m, 2H), 7.73 (s, 1H).

Example 66{4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (34 mg) was reacted with 4-(1 pyrrolidinyl)piperidine as in GeneralProcedure 8 to give the title compound as a pale yellow solid (47%yield). M.p. 202-204° C., LCMS: m/z=518.10 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.55-1.58 (m, 2H), 1.77-1.84 (m, 4H), 1.88-2.02 (m, 2H),2.2402.30 (m, 1H), 2.56-2.62 (M, 4H), 2.90-3.12 (m, 2H), 3.44-3.48 (m,2H), 3.64-3.68 (m, 2H), 3.77-3.87 (m, 1H), 4.49 (s, 2H), 4.55-4.63 (m,1H), 4.95 (bs, 1H), 6.76 (s, 1H), 6.93-7.09 (m, 3H), 7.39 (dd, J=8.3 Hz,4H), 7.72 (s, 1H), 8.08 (s, 1H).

Example 67{4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone

4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (34 mg) was reacted with 1-methylpiperazine as in General Procedure8 to give the title compound as a pale yellow solid (25% yield). M.p.180° C., LCMS: m/z=464.10 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.32 (s,3H), 2.30-2.49 (m, 4H), 3.46 (t, J=5.0 Hz, 2H), 3.50-3.55 (m, 2H),3.62-3.66 (m, 2H), 3.67-3.83 (m, 2H), 4.50 (s, 2H), 5.02 (bs, 1H), 6.75(s, 1H), 6.86-7.08 (m, 3H), 7.40 (dd, J=8.3 Hz, 4H), 7.72 (s, 1H).

Example 68{4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-morpholin-4-yl-methanone

4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (60 mg) was reacted with morpholine as in General Procedure 8 togive the title compound as a light yellow foam (59% yield). M.p. (foam),LCMS: m/z=451.21 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.444-3.48 (m, 2H),3.62-3.66 (m, 2H), 3.64-3.76 (m, 8H), 4.50 (s, 2H), 5.00 (s, 1H), 6.75(s, 1H), 6.84-7.15 (m, 3H) 7.43 (dd, J=8.3 Hz, 4H), 7.71 (d, J=1.8 Hz,1H).

Example 691-(2,5-Difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(50 mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a beige solid(53% yield). M.p. 192-193° C., LCMS: m/z=437.07 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.34 (s, 3H), 2.52-2.58 (m, 4H, 3.43-3.50 (m, 2H), 3.52-3.59(m, 4H), 3.60-3.65 (m, 2H), 4.47 (s, 2H), 4.90 (s, 1H), 6.62 (m, 2H),6.91-7.09 (m, 3H), 7.52 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.62 (d, J=1.8 Hz,1H), 8.2 (d, J=2.5 Hz, 1H).

Example 701-(2,5-Difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(50 mg) was reacted with4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]-morpholineas in General Procedure 4A to give the title compound as an off-whitesolid (48% yield). M.p. 206-207° C., LCMS: m/z=423.99 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 3.45-3.53 (m, 6H), 3.60-3.67 (m, 2H), 3.80-3.87 (m,4H), 4.48 (s, 2H), 4.86 (s, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.66 (s, 1H),6.89-7.06 (m, 3H), 7.55 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.62 (d, J=1.8 Hz,1H), 8.24 (d, J=2.3 Hz, 1H).

Example 715-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carbonitrile

1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(1.0 g) was reacted with5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-2-carbonitrileas in General Procedure 4A to give the title compound as a bright yellowsolid (24% yield). M.p. 200° C. (dec), LCMS: m/z=364.53 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 3.46-3.52 (m, 2H), 3.62-3.72 (m, 2H), 4.50 (s, 2H),5.12 (s, 1H), 6.70 (s, 1H), 6.92-7.00 (m, 2H), 7.03-7.12 (m, 1H),7.62-7.69 (m, 2H), 7.67 (s, J=3.0 Hz, 1H), 7.75 (m, 1H), 8.73 (d, J=1.5Hz, 1H).

Example 725-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carboxylicacid

5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carbonitrile(45 mg) was hydrolyzed as in General Procedure 9, with the exceptionthat the reaction mixture was heated to 70° C. for three (3) hours.Filtration gave the title compound as a yellowish brown precipitate (63%yield). M.p. 240° C. (dec), LCMS: m/z=383.00 (M+H⁺), ¹H-NMR (DMSO-d₆,400 MHz) δ 3.29-3.38 (m, 2H), 3.42-3.49 (m, 2H), 4.60 (s, 2H), 6.95 (s,1H), 7.03 (s, 1H), 7.12-7.19 (m, 2H), 7.28-7.35 (m, 1H), 7.81 (s, 1H),8.00 (d, J=8.1 Hz, 1H), 8.07 (dd, J=8.1 Hz, 2.0 Hz, 1H), 8.84 (s, 1H).

Example 735-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinicacid ethyl ester

1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(350 mg) was reacted with5-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl esteras in General Procedure 4A to give the title compound as a tan solid(29% yield). M.p. 169-172° C., LCMS: m/z=411.03 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 1.42 (t, J=7.1 Hz, 3H), 3.47-3.52 (m, 2H), 3.62-3.71 (m, 2H),4.42 (q, J=7.1 Hz, 2H), 4.51 (s, 2H), 4.99 (s, 1H), 6.75 (s, 1H),6.91-7.02 (m, 2H), 7.03-7.11 (m, 1H), 7.74 (d, J=2.0 Hz, 1H), 8.28 (d,J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H).

Example 745-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinicacid

5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinicacid ethyl ester (75 mg) was saponified as in General Procedure 7 togive the title compound as a tan solid (22% yield). M.p. 255-260° C.,LCMS: m/z=382.94 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.28-3.36 (m, 2H),3.42-3.50 (m, 2H), 4.60 (s, 2H), 6.84 (s, 1H), 7.02 (s, 1H), 7.12-7.20(m, 2H), 7.26-7.33 (m, 1H), 7.74 (d, J=1.8 Hz, 1H), 8.27 (d, J=2.0 Hz,1H), 8.89-8.93 (m, 2H).

Example 751-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid ethyl ester

1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was combined with Mo(CO)₆ (0.5 eq), DMAP (2.0 eq), and DIEA(2.0 eq) in a mixture of dioxane and ethanol (1:1, v/v) and heated to150° C. in a microwave oven for 15 minutes as described in J. Comb.Chem., 2003, 5, 350-352. The reaction mixture was diluted with ethanoland the black precipitate was filtered. Silica gel chromatography gavethe title compound as a yellow solid (16% yield). M.p. 124-125° C.,LCMS: m/z=334.02 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.33 (t, J=7.0 Hz,3H), 3.32-3.38 (m, 2H), 3.61-3.68 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 4.45(s, 2H), 5.68 (bs, 1H), 6.90-6.99 (m, 2H), 7.01-7.09 (m, 1H), 7.16 (d,J=1.5 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H).

Example 76{5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2-yl}morpholin-4-yl-methanone

5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carboxylicacid (32 mg) was reacted with morpholine as in General Procedure 8 togive the title compound as a yellow solid (26% yield). M.p. 111-113° C.,LCMS: m/z=451.92 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.47-3.53 (m, 2H),3.67-3.76 (m, 8H), 3.77-3.85 (m, 2H), 4.50 (s, 2H), 5.09 (s, 1H), 6.71(d J=1.5 Hz, 1H), 6.92-7.04 (m, 2H), 7.05-7.12 (m, 1H), 7.69-7.74 (m,2H), 7.78-7.83 (m, 2H), 8.60 (d, J=2.3 Hz, 1H).

Example 771-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile

1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(394 mg) was reacted with CuCN as in General Procedure 6 to give thetitle compound as a brown solid (86% yield). M.p. 204-206° C., LCMS:m/z=287.07 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.23-3.37 (m, 2H),3.44-3.50 (m, 2H), 4.49 (s, 2H), 6.82 (s, 1H), 7.09-7.22 (m, 2H),7.25-7.33 (m, 1H), 7.62 (bs, 1H), 7.73 (d, J=1.8 Hz, 1H).

Example 781-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid

1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile(239 mg) was hydrolyzed as in General Procedure 9. Filtration gave thetitle compound as a brown solid (58% yield). M.p. 231° C. (dec), LCMS:m/z=306.00 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.37-3.42 (m, 2H),3.55-3.60 (m, 2H), 4.55 (s, 2H), 6.94 (d, J=1.0 Hz, 1H), 7.22-7.33 (m,2H), 7.40-7.48 (m, 1H), 7.91 (d, J=1.3 Hz, 1 h), 8.31 (bs, 1H).

Example 79[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-methylpiperazin-1-yl)methanone

1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (40 mg) was reacted with 1-methyl piperazine as in GeneralProcedure 8 to give the title compound as an orange foam (65% yield).M.p. (foam), LCMS: m/z=388.08 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.28 (s,3H), 2.32-2.38 (m, 4H), 3.41 (t, J=5.0 Hz, 2H), 3.53-3.61 (m, 4H),3.62-3.65 (m, 2H), 4.44 (s, 2H), 5.07 (bs, 1H), 6.61 (s, 1H), 6.89-6.94(m, 2H), 6.98-7.04 (m, 1H), 7.59 (d, J=1.5 Hz, 1H).

Example 801-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid[2(4-methylpiperazin-1-yl)ethyl]amide

1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (40 mg) was reacted with 2(4-methylpiperazin-1-yl)ethylamine as inGeneral Procedure 8 to give the title compound as an orange foam (82%yield). M.p. (foam), LCMS: m/z=431.09 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ2.28 (s, 3H), 2.41-2.58 (m, 6H), 3.12-3.23 (m, 4H), 3.53-3.39 (m, 2H),3.42-3.51 (m, 2H), 3.58-3.67 (m, 2H), 4.49 (s, 2H), 5.33 s, 1H), 6.72(s, 1H), 6.84-6.91 (m, 2H), 6.93-7.04 (m, 1H), 7.10 (s, 1H), 7.85 (d,J=1.5 Hz, 1H).

Example 817-Iodo-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.0 g) was reactedwith 2,4,5 trifluorobenzyl bromide as in General Procedure 1 to give thetitle compound as a pale yellow solid (55% yield). M.p. 227-228° C.,LCMS: m/z=420.00 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 4.26 (s, 2H), 4.89(bs, 1H), 5.06 (s, 2H), 6.91-7.00 (m, 2H), 7.16 (s, 1H), 7.91 (s, 1H).

Example 827-Iodo-1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(600 mg) was reduced as in General Procedure 3 to give the titlecompound as a white solid (63% yield). M.p. 154-156° C., LCMS:m/z=405.92 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 4.27 (s, 2h), 4.91 (bs,1H), 5.06 (s, 2H), 6.93-7.02 (m, 2H), 7.19 (s, 1H), 7.94 (d, J=1.8 Hz,1H).

Example 837-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(42 mg) was reacted withS)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4A to give the title compound as a white solid(31% yield). M.p. 117-118 LCMS: m/z=550.20 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.48-1.69 (m, 4H), 1.88-2.15 (m, 5H), 2.57-2.70 (m, 3H),2.80-2.92 (m, 1H), 3.42-3.53 (m, 2H), 4.33 (s, 2H), 5.12 (bs, 1H), 5.18(s, 2H), 6.95-7.04 (m, 1H), 7.08-7.14 (m, 1H), 7.22 (s, 1H), 7.41 (d,J=8.1 Hz, 2H), 7.52-7.60 (m, 2H), 8.03 (s, 1H).

Example 84((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-{4-[1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone

7-Iodo-1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(40 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4A to give the title compound as a light orangefoam (28% yield). M.p. foam, LCMS: m/z=536.13 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.47-1.60 (m, 1H), 1.61-1.69 (m, 4H), 1.72-2.12 (m, 5H),2.53-2.71 (m, 3H), 2.80-3.01 (m, 1H), 3.38-3.43 (m, 2H), 3.45-3.51 (m,2H), 3.63 (s, 2H), 4.46 (s, 2H), 4.96 (bs, 1H).6.75 (s, 1 h), 6.94-7.02(m, 1H), 6.91-7.16 (m, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.46-7.54 (m, 2H),7.74 (s, 1H).

Example 857-[4-(4-Methylpiperazine-1-carbonyl)phenyl]-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(42 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a white solid(32% yield). M.p. 238° C., LCMS: m/z=496.00 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.33 (s, 3H), 2.35-2.53 (m, 4H), 3.43-3.58 (m, 2H), 3.72-3.84 (m,2H), 4.33 (s, 2H), 5.11 (s, 1H), 5.30 (s, 2H), 6.97-7.03 (m, 1H),7.05-7.14 (m, 1H), 7.21 (s, 1H), 7.45 (dd, J=8.1 Hz, 4H), 8.02 (s, 1H).

Example 86(4-Methylpiperazin-1-yl)-{4-[1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone

7-Iodo-1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(40 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a pale yellowfoam (30% yield). M.p. (foam), LCMS: m/z=482.10 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.33 (s, 3H), 2.35-2.52 (m, 4H), 3.39-3.42 (m, 2H), 3.42-3.56(m, 2H), 3.58-3.66 (m, 2H), 3.68-3.88 (m, 2H), 4.45 (s, 2H), 4.98 (s,1H), 6.72 (s, 1H), 6.89-7.02 (m, 1H), 7.08-7.15 (m, 1H), 7.35-7.44 (m,4H), 7.70 (s, 1H).

Example 87(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (614 mg) was reacted with2,5-difluorobenzoyl chloride as in General Procedure 2 to give the titlecompound as an off-white foam (47% yield). M.p. foam, LCMS: m/z=402.20(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.70-1.90 (m, 2H), 3.50-3.65 (m, 2H),5.29 (bs, 1H), 6.99 (s, 1H), 7.10-7.18 (m, 2H), 7.20-7.25 (m, 1H), 7.99(s, 1H).

Example 88(2,5-Difluorophenyl)-{7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-methanone

(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone(35 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a light yellowsolid (36% yield). M.p. 201-203° C., LCMS: m/z=478.10 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 2.32 (s, 3H), 2.33-2.52 (m, 4H), 3.40-3.85 (m, 8H),5.31 (s, 1H), 6.70-7.05 (m, 3H), 7.15 (s, 1H), 7.24-7.45 (m, 4H), 8.09(s, 1H).

Example 89(2,5-Difluorophenyl)-{7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-methanone

(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone(30 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4A to give the title compound as tan film (13%yield). M.p. (film), LCMS: m/z=532.10 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.76-1.88 (m, 4H), 1.90-2.15 (m, 5H), 2.62-2.73 (m, 4H), 2.90-2.99 (m,1H), 3.38-3.75 (m, 5H), 4.40-4.45 (m, 1H), 5.35 (s, 1H), 6.72-6.98 (m,3H), 7.15 (s, 1H), 7.27-7.53 (m, 4H), 8.09 (s, 1H).

Example 90 2-(5-Iodo-3-nitro-pyridin-2-ylamino)-2-methyl-propionic acidmethyl ester

2-Chloro-5-iodo-3-nitro-pyridine (1.61 g) was dissolved in ethanol.Methyl α-aminoisobutyrate HCl was added (2.4 eq) followed bytriethylamine (2.4 eq). The reaction mixture was heated to 150° C. in amicrowave oven for 30 minutes. The reaction mixture was concentrated todryness and triturated with H₂O. Silica gel chromatography of theresulting brown solid afforded the title compound as a bright yellowcrystalline solid (78% yield based on recovered starting material). M.p.121-122° C., ¹H-NMR (CDCl₃, 400 MHz) δ 1.56 (s, 3H), 1.66 (s, 3H), 3.67(s, 3H), 8.53 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H).

Example 91 7-Iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

2-(5-Iodo-3-nitro-pyridin-2-ylamino)-2-methyl-propionic acid methylester (618 mg) was dissolved in ethanol. SnCl₂2H₂O (5 eq) was added andthe reaction mixture was heated to 80° C. for three (3) hours. Theresulting precipitate was filtered and washed with ethanol to give thetitle compound as an off-white solid (46% yield). M.p.>300° C., LCMS:m/z=304.30 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.29 (s, 6H), 7.11 (bs,1H), 7.16 (d, J=1.8 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 10.38 (bs, 1H).

Example 921-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (237 mg)was reacted with 2,5-difluorobenzyl bromide as in General Procedure 1 togive the title compound as a white solid (98% yield). M.p. 198-201° C.,LCMS: m/z=430.00 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.36 (s, 6H), 5.12(s, 2H), 6.79-6.83 (m, 1H), 7.15-7.22 (m, 1H), 7.28-7.32 (m, 1H), 7.31(s, 1H), 7.40 (s, 1H), 7.90 (s, 1H).

Example 931-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(60 mg) was reduced as in General Procedure 3 to give the title compoundas a white solid (53% yield). M.p. 168-169° C., LCMS: m/z=415.98 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 1.27 (s, 6H), 3.05 (s, 2H), 4.41 (s, 2H), 4.64(s, 1H), 6.79 (s, 1H), 6.92-6.98 (m, 2H), 7.02-7.10 (m, 1H), 7.63 (d,J=1.0 Hz, 1H).

Example 941-(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(45 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4A to give the title compound as a white solid(31% yield). M.p. 171-172° C., LCMS: m/z=560.16 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 1.56 (s, 6H), 1.72-1.83 (m, 4H), 1.90-2.02 (m, 3H), 2.08-2.30(m, 2H), 2.58-2.68 (m, 4H), 2.85-2.92 (m, 1H), 3.36-3.56 (m, 2H),4.43-4.48 (m, 1H), 5.01 (s, 1H), 5.21 (s, 2H), 6.84-6.88 (m, 1H),6.91-6.97 (m, 1H), 7.04-7.11 (m, 1H), 7.20 (1.5 Hz, 1H), 7.41 (d, J=8.4Hz, 2H), 7.52-7.58 (m, 2H), 8.04 (d, J=1.5 Hz, 1H).

Example 951-(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(45 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a white solid(55% yield). M.p. 204-206° C., LCMS: m/z=506.16 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 1.56 (s, 6H), 2.33 (s, 3H), 2.36-2.54 (m, 4H), 3.36-3.54 (m,2H), 3.73-3.83 (m, 2H), 5.14 (s, 1H), 5.21 (s, 2H), 6.84-6.88 (m, 1H),6.93-6.98 (m, 1H), 7.07-7.13 (m, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.43 (m,4H), 8.03 (d, J=2.0 Hz, 1H).

Example 96{4-[1-(2,5-Difluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone

1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(44 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4A to give the title compound as a light yellowsolid (11% yield). M.p. 74-77° C., LCMS: m/z=546.15 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 1.26 (s, 6H), 1.70-1.83 (m, 4H), 1.85-1.99 (m, 4H),2.00-2.16 (m, 2H), 2.58-2.69 (m, 4H), 2.82-2.94 (m, 1H), 3.13 (s, 2H),3.46-3.54 (m, 2H), 4.52 (s, 2H), 4.77 (bs, 1H), 6.80 (s, 1H), 6.94-6.96(m, 1H), 7.03-7.07 (m, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.42-7.53 (m, 2H),7.74 (s, 1H).

Example 97{4-[1-(2,5-Difluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone

1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(44 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as an off-whitesolid (55% yield). M.p. 191-192° C., LCMS: m/z=492.10 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 1.34 (s, 6H), 2.32 (s, 3H), 2.38-2.50 (m, 4H), 3.13(s, 2H), 3.45-3.58 (m, 2H), 3.65-3.85 (m, 2H), 4.52 (s, 2H), 4.90 (bs,1H), 6.79 (d, J=1.3 Hz, 1H), 6.90-6.97 (m, 1H), 6.99-7.08 (m, 2H), 7.42(dd, J=8.6 Hz, 4H), 7.74 (d, J=1.5 Hz, 1H).

Example 981-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(348 mg) was reduced as in General Procedure 3 to give the titlecompound as an off-white solid (42% yield). M.p. 156-157° C., LCMS:m/z=422.00 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.12-3.20 (m, 2H),3.42-3.50 (m, 2H), 4.41 (s, 2H), 4.89 (bs, 1H), 6.98-7.05 (m, 1H), 7.08(s, 1H), 7.10-7.18 (m, 1H), 7.62 (d, J=1.5 Hz, 1H).

Example 99{4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(42 mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a pale yellowfoam (36% yield). M.p. 93-95° C., LCMS: m/z=553.00 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 1.75-1.85 (m, 5H), 1.87-2.04 (m, 2H), 2.22-2.33 (m,1H), 2.88-3.08 (m, 2H), 3.28-3.33 (m, 2H), 3.52-3.58 (m, 2H), 3.82-3.90(m, 1H), 4.53 (s, 1H), 4.90 (bs, 1H), 6.96-7.02 (m, 1H), 7.17 (s, 1H),7.18-7.20 (m, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.75(s, 1H).

Example 100{4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(42 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4A to give the title compound as a pale yellowfoam (33% yield). M.p. (foam), LCMS: m/z=553.00 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 1.73-1.80 (m, 4H), 1.90-2.04 (m, 3H), 2.10-2.29 (m, 2H),2.58-2.70 (m, 4H), 2.85-2.95 (m, 1H), 3.26-3.33 (m, 2H), 3.48-3.58 (m,2H), 4.42-4.50 (m, 1H), 4.53 (s, 2H), 4.95 (s, 1H), 6.96-7.04 (m, 1H),7.11 (s, 1H), 7.10-7.18 (m, 1H), 7.47-7.56 (m, 4H), 7.74 (s, 1H).

Example 1011-(2-Chloro-3,6-difluorobenzyl)-7-(3-chloro-2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with4-[3-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholineas in General Procedure 4A to give the title compound as a tan foam (49%yield). M.p. (foam), LCMS: m/z=493.59 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.28 (t, J=5.3 Hz, 2H), 3.38 (t, J=4.8 Hz, 4H), 3.52-3.58 (m, 2H), 3.89(t, J=4.3 Hz, 4H), 4.47 (d, J=1.3 Hz, 2H), 5.16 (bs, 1H), 6.89 (d, J=5.0Hz, 1H), 6.97-7.06 (m, 2H), 7.08-7.15 (m, 1H), 7.56 (d, J=1.8 Hz, 1H),8.17 (d, J=5.0 Hz, 1H).

Example 1021-(2-Chloro-3,6-difluorobenzyl)-7-(3-fluoro-2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with4-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholineas in General Procedure 4A to give the title compound as a tan foam (35%yield). M.p. (foam), LCMS: m/z=476.02 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.28 (t, J=4.8 Hz, 2H), 3.48 (t, J=4.8 Hz, 4H), 3.52-3.65 (m, 2H), 3.87(t, J=4.6 Hz, 4H), 4.50 (s, 2H), 5.38 (bs, 1H), 6.82-6.86 (m, 1H),6.97-7.04 (m, 1H), 7.08 (s, 1H), 7.04-7.15 (m, 1H), 7.70 (s, 1H), 8.00(d, J=5.0 Hz, 1H).

Example 1031-(2-Chloro-3,6-difluorobenzyl)-7-(3,5-dimethyl-isoxazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(75 mg) was reacted with 3,5-dimethylisoxazole-4 boronic acid as inGeneral Procedure 4A to give the title compound as a pale yellow solid(45% yield). M.p. 215-216° C., LCMS: m/z=393.42 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.22 (s, 3H), 2.36 (s, 3H), 3.31 (t, J=5.0 Hz, 2H), 3.52-3.58(m, 2H), 4.47 (s, 2H), 4.98 (bs, 1H), 6.71 (s, 1H), 6.98-7.05 (m, 1H),7.09-7.17 (m, 1H), 7.36 (d, J=1.3 Hz, 1H).

Example 104{4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a pale yellowfoam (17% yield). M.p. (foam), LCMS: m/z=499.43 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.33 (s, 3H), 2.36-2.52 (m, 4H), 3.26-3.33 (m, 2H), 3.52-3.56(m, 2H), 3.52-3.86 (m, 4H), 4.53 (s, 2H), 5.00 (bs, 1H), 6.97-7.04 (m,1H), 7.10 (s, 1H), 7.11-7.17 (m, 1H), 7.44 (dd, J=8.4 Hz, 1.8 Hz, 2H),7.52 (dd, J=8.3 Hz, 1.8 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H).

Example 1051-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with 2-(4-morpholino)pyridine-5-boronic acidpinacol ester as in General Procedure 4A to give the title compound as abeige foam (52% yield). M.p. (foam), LCMS: m/z=458.04 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 3.28-3.34 (m, 2H), 3.51-3.59 (m, 6H), 3.81-3.88 (m,4H), 4.54 (s, 2H), 5.30 (s, 1H), 6.69 (d, J=8.8 Hz, 1H), 7.00-7.08 (m,2H), 7.11-7.18 (m, 1H), 7.53 (s, 1H), 7.61 (dd, J=8.8 Hz, 2.5 Hz, 1H),8.33 (s, J=2.2 Hz, 1H).

Example 1061-(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)-pyrimidin-5-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronicacid pinacol ester as in General Procedure 4A to give the title compoundas a pale orange solid (27% yield). M.p. 194-195° C., LCMS: m/z=472.09(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.38 (s, 3H), 2.51-2.58 (m, 4H), 3.31(t, J=4.8 Hz, 2H), 3.49-3.58 (m, 2H), 3.89-3.97 (m, 4H), 4.51 (s, 2H),4.95 (bs, 1H), 6.96 (s, 1H), 6.99-7.08 (m, 1H), 7.10-7.18 (m, 1H), 7.57(s, 1H), 8.45 (s, 1H).

Example 1071-(2-Chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyrimidin-5-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with 2-(4-morpholino)pyrimidine-5-boronic acidpinacol ester as in General Procedure 4A to give the title compound asan off-white solid (27% yield). M.p. 250-251° C., LCMS: m/z=459.17(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.29-3.35 (m, 2H), 3.52-3.56 (m, 2H),3.78-3.84 (m, 8H), 4.51 (s, 2H), 4.86 (bs, 1H), 6.96 (s, 1H), 7.00-7.08(m, 1H), 7.10-7.17 (m, 1H), 7.59 (d, J=1.8 Hz, 1H), 8.46 (s, 1H).

Example 1081-(2-Chloro-3,6-difluorobenzyl)-7-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with 4-morpholine phenyl-boronic acid pinacol esteras in General Procedure 4A to give the title compound as a pale yellowsolid (49% yield). M.p. 217-219° C., LCMS: m/z=456.56 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 3.19 (t, J=4.8 Hz, 4H), 3.27 (t, J=4.8 Hz, 2H),3.49-3.55 (m, 2H), 3.88 (t, J=4.6 Hz, 4H), 4.52 (s, 2H), 4.78 (bs, 1H),6.96 (d, J=8.8 Hz, 2H), 6.98-7.05 (m, 1H), 7.09 (s, 1H), 7.10-7.15 (m,1H), 7.42 (d, J=8.6 Hz, 2H), 7.70 (d, J=1.5 Hz, 1H).

Example 1097-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (704 mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a yellow solid(20% yield). M.p. 225° C. (dec), LCMS: m/z=311.13 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.35 (s, 3H), 2.49-2.56 (m, 4H), 3.36-3.42 (m, 2H), 3.53-3.63(m, 6H), 4.90 (bs, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.77 (d, J=1.5 Hz, 1H),7.58 (dd, J=8.8 Hz, 2.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 8.31 (d, J=2.0Hz, 1H).

Example 1101-(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)-2-phenylethanone

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted withphenyl acetyl chloride as in General Procedure 2 to give the titlecompound as a pale yellow foam (31% yield). M.p. (foam), LCMS:m/z=379.86 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.32-3.45 (m, 2H),3.75-3.85 (m, 2H), 3.87 (s, 2H), 5.25 (bs, 1H), 7.21-7.38 (m, 5H), 8.01(s, 1H).

Example 1112-Phenyl-1-{7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-ethanone

1-(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)-2-phenylethanone (30mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a white foam(52% yield). M.p. (foam), LCMS: m/z=510.13 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.47-1.62 (m, 2H), 1.75-2.05 (m, 3H), 2.22-2.29 (m, 1H),2.53-2.62 (m, 5H), 2.82-3.10 (m, 3H), 3.33-3.52 (m, 2H), 3.71-3.88 (m,3H), 3.95 (s, 2H), 4.51-4.63 (m, 1H), 5.25 (bs, 1H), 7.12-7.34 (m, 5H),7.35-7.48 (m, 4H), 8.16 (s, 1H).

Example 1122-(2,5-Difluorophenyl)-1-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)ethanone

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with2,5-difluorophenyl acetyl chloride as in General Procedure 2 to give thetitle compound as an off-white solid (14% yield). M.p. 152-153° C.,LCMS: m/z=415.90 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.47-3.54 (m, 2H),3.80-3.87 (m, 4H), 5.44 (bs, 1H), 6.90-7.04 (m, 3H), 8.03 (s, 1H).

Example 1132-(2,5-Difluorophenyl)-1-{7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}ethanone

2-(2,5-Difluorophenyl)-1-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)-ethanone(30 mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a light yellowsolid (15% yield). M.p.>300° C., LCMS: m/z=465.02 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.36 (s, 3H), 2.52-2.57 (m, 2H), 3.52-3.62 (m, 6H), 3.90-3.96(m, 4H), 5.11 (bs, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.90-7.04 (m, 3H),7.41-7.58 (m, 2H), 8.07 (s, 1H), 8.32 (s, 1H).

Example 1142-(2,5-Difluorophenyl)-1-{7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}ethanone

2-(2,5-Difluorophenyl)-1-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)ethanone(30 mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a white foam(20% yield). M.p. (foam), LCMS: m/z=546.09 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.42-1.72 (m, 6H), 2.22-2.42 (m, 2H), 2.54-2.64 (m, 5H),2.85-3.11 (m, 3H), 3.56-3.62 (m, 2H), 3.88-3.92 (m, 4H), 4.55-4.66 (m,1H), 5.23 (s, 1H), 6.91-7.07 (m, 3H), 7.41-7.49 (m, 4H), 8.16 (s, 1H).

Example 1151-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (968 mg) was reactedwith 5-chloro-2-(trifluoromethyl)benzyl bromide as in GeneralProcedure 1. The resulting1-(2-chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-onewas reduced as in General Procedure 2 to give the title compound as anorange solid (17% yield). M.p. 189-191° C., LCMS: m/z=454.08 (M+H⁺),¹H-NMR (DMSO-d₆, 400 MHz) δ 3.28-3.34 (m, 2H), 3.41-3.46 (m, 2H), 4.53(s, 2H), 6.52 (s, 1H), 6.75 (s, 1H), 7.44 (s, 2H), 7.59 (d, J=8.4 Hz,1H), 7.82 (d, J=8.6 Hz, 1H).

Example 1161-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (924 mg) was reactedwith 2-chloro-5-(trifluoromethyl)benzyl bromide as in General Procedure1 to give the title compound as a white solid (39% yield). M.p. 252-253°C., LCMS: m/z=468.02 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.16 (d, J=1.2Hz, 2H), 5.16 (s, 2H), 7.20 (s, 1H), 7.26 (d, J=1.3 Hz, 1H), 7.42 (s,1H), 7.71 (dd, J=8.3 Hz, 1.5 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.83 (d,J=1.5 Hz, 1H).

Example 117{4-[1-(5-Chloro-2-trifluoromethylbenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

1-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(40 mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as an orange foam(19% yield). M.p. (foam), LCMS: m/z=487.19, ¹H-NMR (CDCl₃, 400 MHz) δ1.43-1.62 (m, 3H), 1.65-1.99 (m, 3H), 2.21-2.30 (m, 2H), 2.52-2.61 (m,6H), 2.87-3.08 (m, 3H), 3.47-3.51 (m, 2H), 3.65-3.71 (m, 2H), 4.62 (s,2H), 5.02 (s, 1H), 6.59 (d, J=1.5 Hz, 1H), 7.31-7.39 (m, 5H), 7.50 (s,1H), 7.65 (d, J=8.4 Hz, 1H), 7.74 (s, 1H).

Example 1181-(5-Chloro-2-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(40 mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a pale orangesolid (28% yield). M.p. 226-227° C., LCMS: m/z=503.90 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 2.34 (s, 3H), 2.51 (t, J=5.0 Hz, 4H), 3.47-3.56 (m,6H), 3.62-3.69 (m, 2H), 4.61 (s, 2H), 4.92 (bs, 1H), 6.49 (d, J=1.0 Hz,1H), 6.64 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.52-7.58 (m, 2H),7.61-7.65 (m, 2H), 8.18 (d, J=2.3 Hz, 1H).

Example 1191-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(590 mg) was reduced as in General Procedure 2 to give the titlecompound as a yellow solid (28% yield). M.p. 120-125° C., LCMS:m/z=454.01 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.38 (t, J=5.0 Hz, 2H),3.55-3.61 (m, 2H), 4.45 (s, 2H), 5.11 (s, 1H), 6.66 (s, 1H), 7.47 (s,1H), 7.53 (dd, J=8.3 Hz, 2H), 7.62 (d, J=1.8 Hz, 1H).

Example 1201-(2-Chloro-5-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(40 mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a yellow film(13% yield). M.p. (film), LCMS: m/z=502.98 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.34 (s, 3H), 2.51 (t, J=5.3 Hz, 4H), 3.28 (t, J=5.3 Hz, 2H),3.54 (t, J=5.0 Hz, 4H), 3.66-3.72 (m, 2H), 4.53 (s, 2H), 4.89 (bs, 1H),6.53 (s, 1H), 6.64 (d, J=8.8 Hz, 1H), 7.46-7.54 (m, 4H), 7.63 (d, J=1.8Hz, 1H), 8.18 (d, J=2.3 Hz, 1H).

Example 1211-(2,5-Difluorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was dissolved inanhydrous pyridine. 2,5-difluorobenzene sulfonyl chloride (1.0 eq) wasadded and the mixture stirred at room temperature for 16 hours. Thereaction mixture was concentrated and purified by column chromatographyto give the title compound as a pale yellow solid (13% yield). M.p.187-188° C., LCMS: m/z=437.73 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.29-3.33 (m, 2H), 3.83 (t, J=4.8 Hz, 2H), 5.08 (bs, 1H), 7.11-7.19 (m,1H), 7.26-7.33 (m, 1H), 7.58-7.63 (m, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.03(d, J=1.8 Hz, 1H).

Example 1221-(2,5-Difluorobenzenesulfonyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Difluorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(50 mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to methyl-piperazine as a yellow foam (35%yield). M.p. (foam), LCMS: m/z=487.04 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ2.34 (s, 3H), 2.54 (t, J=5.3 Hz, 4H), 3.35-3.38 (m, 2H), 3.60 (t, J=5.0Hz, 4H), 3.91 (t, J=4.8 Hz, 2H), 5.05 (bs, 1H), 6.71 (d, J=8.8 Hz, 1H),7.11-7.17 (m, 1H), 7.24-7.29 (m, 1H), 7.58-7.63 (m, 2H), 7.90 (d, J=2.0Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 8.34 (d, J=2.6 Hz, 1H).

Example 1231-Benzenesulfonyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved inanhydrous pyridine. Phenylsulfonyl chloride (1.0 eq) was added and thereaction mixture was heated to 100° C. in a microwave oven for 10minutes. Silica gel chromatography gave the title compound as a paleorange solid (23% yield). M.p. 145-146° C., LCMS: m/z=407.71 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 2.94-2.99 (m, 2H), 3.74 (t, J=5.0 Hz, 2H),4.83 (bs, 1H), 7.45-7.49 (m, 2H), 7.58-7.65 (m, 3H), 8.06 (d, J=2.0 Hz,1H), 8.17 (d, J=2.0 Hz, 1H).

Example 1241-(2-Chlorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved inanhydrous pyridine. 2-chlorobenzene sulfonyl chloride (1.0 eq) was addedand the reaction mixture was heated to 100° C. in a microwave oven for10 minutes. Silica gel chromatography gave the title compound as a paleorange solid (10% yield). M.p. 146-147° C., LCMS: m/z=435.94 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 3.30-3.35 (m, 2H), 3.80 (t, J=5.0 Hz, 2H),5.02 (bs, 1H), 7.42-4.57 (m, 3H), 7.81 (d, J=1.8 Hz, 1H), 8.00 (d, J=1.8Hz, 1H), 8.10 (dd, J=8.6 Hz, 1.5 Hz, 1H).

Example 1251-Benzenesulfonyl-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-Benzenesulfonyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg)was reacted with1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a yellow foam(72% yield). M.p. (foam), LCMS: m/z=450-98 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.39 (s, 3H), 2.60 (t, J=5.0 Hz, 4H), 2.98-3.03 (m, 2H), 3.64 (t,J=5.0 Hz, 4H), 3.80 (t, J=5.0 Hz, 2H), 5.16 (bs, 1H), 6.73 (d, J=8.8 Hz,1H), 7.40-7.45 (m, 2H), 7.51-7.54 (m, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.67(dd, J=8.8 Hz, 2,5 Hz, 1H), 8.08 (s, 1H), 8.40 (d, J=2.0 Hz, 1H).

Example 1261-(2-Chlorobenzenesulfonyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4tetrahydropyrido[2,3-b]pyrazine

1-(2-Chlorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(44 mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a yellow solid(41% yield). M.p. 164-165° C., LCMS: m/z=486.79 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.36 (s, 3H), 2.54 (t, J=5.1 Hz, 4H), 3.39-3.42 (m, 2H), 3.60(t, J=4.5 Hz, 4H), 3.88 (t, J=4.5 Hz, 2H), 5.17 (bs, 1H), 6.69 (d, J=8.8Hz, 1H), 7.39-7.45 (m, 1H), 7.51-7.56 (m, 3H), 7.73 (s, 1H), 8.01 (d,J=1.0 Hz, 1H), 8.13 (dd, J=8.6 Hz, 1.0 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H).

Example 1271-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile

1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(2.0 g) was reacted with CuCN as in General Procedure 6 to give thetitle compound as an off-white solid (46% yield). M.p. 221-222° C.,LCMS: m/z=320.77 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.28 (t, J=4.6 Hz,2H), 3.45-3.54 (m, 2H), 4.48 (s, 2H), 6.69 (s, 1H), 7.29 (d, J=2.5 Hz,1H), 7.41 (dd, J=8.6 Hz, 2.5 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.67 (bs,1H), 7.75 (d, J=1.8 Hz, 1H).

Example 1281-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid

1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile(680 mg) was hydrolyzed as in General Procedure 9. Filtration gave thetitle compound as an orange solid (quantitative yield). M.p. 273° C.(dec), LCMS: m/z=340.23 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.48-3.53(m, 2H), 3.61-3.71 (m, 2H), 4.62 (s, 2H), 6.87 (s, 1H), 7.42 (d, J=7.6Hz, 1H), 7.43 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.88 (s, 1H), 9.33 (bs,1H), 13.20 (bs, 1H).

Example 1291-(2,5-Dichlorobenzyl)-7-(2-methoxypyrimidin-5-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(500 mg) was reacted with 2-methoxypyrimidine-5-boronic acid as inGeneral Procedure 4A to give the title compound as a pale orange foam in42% yield. M.p. (foam), LCMS: m/z=404.36 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz)δ 3.51 (t, J=5.3 Hz, 2H), 3.66-3.70 (m, 2H), 4.01 (s, 3H), 4.49 (s, 2H),4.99 (bs, 1H), 6.46 (d, J=1.5 Hz, 1H), 7.18-7.26 (m, 2H), 7.35 (d, J=8.3Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 8.50 (s, 1H).

Example 1304-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(300 mg) was reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester as in General Procedure 4A to give the titlecompound as a beige solid (35% yield). M.p. 92-95° C., LCMS: m/z=477.28(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.47 (s, 9H), 2.32-2.38 (m, 2H),3.39-3.46 (m, 2H), 3.52-3.59 (m, 2H), 3.60-3.65 (m, 2H), 3.95-3.99 (m,2H), 4.43 (s, 2H), 5.18 (s, 1H), 5.69-5.72 (m, 1H); 6.43 (s, 1H),7.17-7.20 (m, 1H), 7.23 (s, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.50 (s, 1H).

Example 1311-(2,5-Dichlorobenzyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (105 mg) was dissolved in CH₂Cl₂/trifluoroaceticacid (3:1, v/v) and stirred at room temperature for two (2) hours. Thereaction mixture was concentrated, diluted with CH₂Cl₂, washed withNaHCO₃ (×2), dried, filtered, and concentrated to give the titlecompound as a pale orange solid (84% yield). M.p. 133-136° C., LCMS:m/z=375.13 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 2.30-2.38 (m, 2H),3.00-3.06 (m, 1H), 3.28-3.34 (m, 2H), 3.52-3.58 (m, 2H), 4.49 (s, 2H),5.80 (s, 1H), 6.47 (s, 1H), 6.59 (s, 1H), 7.29 (d, J=2.5 Hz, 1H),7.37-7.42 (m, 2H), 7.54 (d, J=8.6 Hz, 1H).

Example 132{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone

1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4A to give the title compound as a pale yellowfoam (49% yield). M.p. (foam), LCMS: m/z=498.07 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.31 (s, 3H), 2.32-2.50 (m, 4H), 3.44-3.51 (m, 2H), 3.45-3.84(m, 4H), 3.63-3.68 (m, 2H), 4.49 (s, 2H), 5.21 (s, 1H), 6.62 (d, J=1.5Hz, 1H), 7.18-7.21 (m, 1H), 7.24-7.29 (m, 1H), 7.34 (d, J=8.6 Hz, 1H),7.39-7.42 (m, 4H), 7.72 (d, J=1.8 Hz, 1H).

Example 1331-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.07 g) was reactedwith 5-fluoro-2-trifluoromethylbenzyl bromide as in General Procedure 1to give the title compound as an off-white solid (51% yield). M.p.244-245° C., LCMS: m/z=453.03 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.21(s, 2H), 5.15 (s, 2H), 6.97 (s, 1H0, 7.12 (d, J=9.8 Hz, 1H), 7.25 (s,1H), 7.36 (dd, J=8.3 Hz, 1H), 7.84 (s, 1H), 7.88-7.94 (m, 1H).

Example 1341-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-2-ol

1-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(870 mg) was reduced as in General Procedure 3 to give the titlecompound as an off-white solid (30% yield). M.p. 142° C. (dec), LCMS:m/z=455.10 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.51 (d, J=11.4 Hz, 1H),3.61 (dd, J=11.4 Hz, 1.5 Hz, 1H), 4.57 (d, J=18.2 Hz, 1H), 4.87 (d,J=18.2 Hz, 1H), 4.95 (s, 1H), 5.32 (bs, 1H), 6.49 (d, J=1.6 Hz, 1H),7.01-7.11 (m, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.73 (dd, J=8.6 Hz, 3.3 Hz,1H).

Example 135 4-(2-Oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid ethyl ester

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (520 mg) was reactedwith 4-ethoxycarbonylphenyl boronic acid as in General Procedure 4B togive the title compound as a light yellow solid in 79% yield. M.p.>200°C., LCMS: m/z=298.14 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.33 (3H, t,J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 7.26 (1H, d, J=2.0 Hz), 7.67 (2H, d,J=8.3 Hz), 7.99 (2H, d, J=8.1 Hz), 8.04 (1H, d, J=2.3 Hz).

Example 1361-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (500 mg) was treatedwith 2,6-dichlorobenzyl bromide as in General Procedure 1 to give thetitle compound as an off-white solid. M.p.>200° C., LCMS: m/z=434.37(M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.30 (2H, s), 5.29 (2H, s), 7.31(1H, d, J=8.6 Hz), 7.34 (1H, d, J=7.6 Hz), 7.45 (1H, s), 7.47 (1H, s),7.76 (1H, d, J=1.0 Hz).

Example 1371-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(150 mg) was reacted with pyridine-3-boronic acid as in GeneralProcedure 4B to give the title compound as a brown solid. M.p.>200° C.,LCMS: m/z=385.48 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.06 (2H, s), 5.45(2H, s), 7.07 (1H, s), 7.45 (5H, m), 7.85 (1H, d, J=7.8 Hz), 8.01 (1H,s), 8.49 (1H, d, J=4.8 Hz), 8.67 (1H, s) (NMR and LCMS indicate presenceof triphenylphosphine impurity)

Example 1381-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine,trifluoroacetic acid salt

1-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(83 mg) was reduced as in General Procedure 3 to give the title compoundas a green solid after preparative reversed-phase HPLC purification (3%yield). LCMS: m/z=371.35 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.24 (2H, t,J=4.9 Hz), 3.62 (2H, t, J=4.9 Hz), 4.72 (2H, s), 7.19 (1H, s), 7.43 (2H,d, J=8.1 Hz), 7.47 (1H, d, J=1.5 Hz), 7.54 (1H, m), 7.96 (1H, m), 8.65(1H, d, J=4.3 Hz), 8.80 (1H, s).

Example 1394-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester

1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(231 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as inGeneral Procedure 4B to give the title compound as a yellow solid.M.p.=226° C., LCMS: m/z=456.52 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.35(3H, t, J=6.9 Hz), 4.09 (3H, s), 4.33 (3H, q, J=7.1 Hz), 5.47 (2H, s),7.32 (2H, m), 7.48 (2H, d, J=8.1 Hz), 7.57 (3H, m), 7.63 (1H, m), 7.90(1H, m), 7.98 (2H, d, J=8.2 Hz), 8.03 (1H, d, J=2.0 Hz).

Example 1404-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid

4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester (243 mg) was saponified as in General Procedure 7 togive the title compound as an off-white solid (87% yield). M.p.>200° C.,LCMS: m/z=428.47 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.07 (2H, d, J=1.3Hz), 5.44 (2H, s), 7.10 (1H, bs), 7.32 (2H, m), 7.48 (2H, d, J=8.1 Hz),7.54 (2H, d, J=8.3 Hz), 7.95 (2H, d, J=8.3 Hz), 8.03 (1H, d, J=2.0 Hz).

Example 141S-1-(2,6-Dichlorobenzyl)-7-[4-((2-pyrrolidin-1-yl)methylpyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (43 mg) was coupled to (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidineas in General Procedure 8 to give the title compound as a brown solid(41% yield). M.p.=188° C., LCMS: m/z=564.07 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 0.88 (1H, m), 1.26 (2H, m), 1.76 (5H, m), 2.04 (6H, m), 2.23 (1H,m), 2.64 (4H, m), 2.89 (1H, m), 3.49 (3H, m), 4.25 (2H, s), 4.45 (1H,bs), 4.84 (1H, bs), 5.56 (2H, s), 7.16 (1H, m), 7.33 (4H, m), 7.52 (2H,d, J=8.3 Hz), 7.94 (1H, d, J=1.5 Hz).

Example 1424-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin-1-yl-ethyl)benzamide

4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (40 mg) was coupled to 2-pyrrolidin-1-yl-ethylamine as in GeneralProcedure 8 to give the title compound as an off-white solid (26%yield). M.p.>200° C., LCMS: m/z=524.11 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.82 (4H, m), 2.60 (4H, m), 2.74 (2H, m), 3.59 (2H, m), 4.26 (2H, s),4.85 (1H, bs), 5.56 (2H, s), 7.16 (1H, m), 7.32 (2H, d, J=8.1 Hz), 7.39(2H, d, J=8.3 Hz), 7.82 (2H, d, J=8.3 Hz), 7.96 (1H, d, J=1.8 Hz).

Example 1434-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(6-dimethylaminohexyl)benzamide,trifluoroacetic acid salt

4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (43 mg) was coupled to 3-dimethylaminohexylamine as in GeneralProcedure 8 to give the title compound as an off-white solid afterpreparative reversed-phase HPLC purification (33% yield). M.p.=150° C.,LCMS: m/z=554.28 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.47 (4H, m), 1.71(4H, m), 2.88 (6H, s), 3.13 (2H, t, J=8.1 Hz), 3.41 (2H, t, J=7.1 Hz),4.30 (2H, s), 5.63 (2H, s), 7.28 (1H, m), 7.42 (3H, m), 7.48 (2H, d,J=8.3 Hz), 7.88 (3H, m).

Example 1444-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(4-dimethylaminobutyl)benzamide,trifluoroacetic acid salt

4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (36 mg) was coupled to 3-Dimethylaminobutylamine as in GeneralProcedure 8 to give the title compound as a tan solid after preparativereversed-phase HPLC purification (50% yield). M.p.=147° C., LCMS:m/z=526.11 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.71 (2H, m), 1.80 (2H, m),2.90 (6H, s), 3.20 (2H, t, J=7.8 Hz), 3.46 (2H, t, J=6.7 Hz), 4.35 (2H,s), 5.64 (2H, s), 7.29 (1H, t, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.48(2H, d, J=6.1 Hz), 7.51 (1H, s), 7.89 (2H, s), 7.90 (1H, s).

Example 1457-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (297 mg) was alkylatedwith 1-(1-bromoethyl)-2,4,5-trifluorobenzene as in General Procedure 1to give the title compound.

Example 1467-[4-(4-Methylpiperazine-1-carbonyl)phenyl]-1-[1-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(45 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a colorlesssolid after preparative reversed-phase HPLC purification (15% yield).LCMS: m/z=510.11 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.91 (3H, d, J=7.1Hz), 2.96 (3H, s), 3.22 (2H, m), 3.52 (3H, m), 4.28 (2H, d), 6.22 (1H,m), 7.17 (1H, m), 7.64 (5H, m), 7.82 (1H, s), 7.93 (1H, s).

Example 1477-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(551 mg) was reduced as in General Procedure 3 to give the titlecompound as a yellow foam (52% yield). LCMS: m/z=419.94 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 1.54 (3H, d, J=6.8 Hz), 3.15 (1H, m), 3.30 (1H, m),3.43 (2H, t, J=4.7 Hz), 5.02 (1H, quartet, J=6.9 Hz), 5.47 (1H, bs),6.86 (1H, s), 6.96 (1H, m), 7.11 (1H, m), 7.55 (1H, d, J=1.5 Hz).

Example 148S-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}-(4-{1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone,trifluoroacetic acid salt

7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(44 mg) was reacted with(S)-2-pyrrolidin-1-yl-methylpyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4B to give the title compound as a yellow solidafter reversed-phase HPLC purification (45% yield). LCMS: m/z=550.09(M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 3.31 (3H, d, J=6.8 Hz), 2.06 (8H, m),3.21 (3H, m), 3.49 (6H, m), 3.74 (1H, m), 4.05 (1H, m), 4.58 (1H, m),5.50 (1H, quartet, J=6.8 Hz), 7.24 (1H, m), 7.41 (1H, s), 7.53 (2H, m),7.69 (4H, m).

Example 149(4-Methylpiperazin-1-yl)-(4-{1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(30 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a yellow solid(2% yield). LCMS: m/z=560.73 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.26 (8H,m), 2.44 (7H, m), 3.64 (4H, m), 7.38 (1H, m), 7.47 (4H, m), 7.61 (4H,m).

Example 1501-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.030 g) was alkylatedwith 2,5-difluoro-alpha-bromoethylbenzene as in General Procedure 1 togive the title compound as a yellow solid. LCMS: m/z=415.93 (M+H⁺)

Example 151S-(4-{1-[1-(2,5-Difluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone

1-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(59 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4B to give the title compound as a yellow solid(4% yield). LCMS: m/z=546.15 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.57 (1H,m), 1.84 (4H, m), 1.89 (3H, d, J=7.1 Hz), 1.98 (3H, m), 2.15 (2H, s),2.71 (4H, m), 2.93 (1H, m), 3.44 (1H, m), 3.61 (1H, m), 4.07 (2H, d,J=4.3 Hz), 4.43 (1H, bs), 6.23 (1H, m), 7.05 (2H, m), 7.49 (6H, m), 7.95(1H, s).

Example 1521-[1-(2,5-Difluorophenyl)ethyl]-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one,trifluoroacetic acid salt

1-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(55 mg) was reacted with(4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a yellow solidafter preparative reversed-phase HPLC purification (7% yield). LCMS:m/z=492.13 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.91 (3H, d, J=7.1 Hz),2.96 (3H, s), 3.22 (5H, m), 3.52 (3H, m), 4.31 (2H, m), 6.32 (1H,quartet, J=6.8 Hz), 7.09 (2H, m), 7.51 (1H, m), 7.58 (4H, m), 7.74 (1H,s), 7.90 (1H, d, J=1.5 Hz).

Example 1531-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(438 mg) was reduced as in General Procedure 3 to give the titlecompound as a yellow solid. LCMS: m/z=402.01 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.55 (3H, d, J=6.8 Hz), 3.34 (2H, m), 3.44 (2H, m), 4.81 (1H, s),5.05 (1H, m), 7.00 (4H, m), 7.58 (1H, d, J=1.5 Hz).

Example 154S-(4-{1-[1-(2,5-Difluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone

1-[1-(2,5-Difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(73 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4B to give the title compound as an orange foam(6% yield). LCMS: m/z=532.12 (M+H⁺), ¹H-NMR (CD₃OD, 400 MHz) δ 1.61 (3H,m), 1.84 (4H, m), 2.03 (3H, m), 2.24 (2H, m), 2.73 (2H, m), 2.94 (1H,m), 3.44 (3H, m), 3.58 (1H, m), 4.15 (4H, m), 4.43 (1H, bs), 5.28 (1H,m), 7.04 (2H, m), 7.14 (1H, m), 7.22 (1H, m), 7.54 (5H, m).

Example 1551-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.012 g) was reactedwith 2,5-dichlorobenzyl bromide as in General Procedure 1 to give thetitle compound as a brown solid (69% yield). M.p.>200° C., LCMS:m/z=434.36 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.18 (2H, s), 5.07 (2H,s), 4.18 (2H, s), 7.14 (1H, d, J=1.8 Hz), 7.15 (1H, d, J=2.3 Hz), 7.40(1H, dd, J=8.6, 2.5 Hz), 7.56 (1H, d, J=8.6 Hz), 7.85 (1H, d, J=1.8 Hz).

Example 1561-(2,5-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(62 mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a brown solid(42% yield). M.p.>200° C., LCMS: m/z=564.14 (M+H⁺), ¹H-NMR (DMSO-d₆, 400MHz) δ 1.37 (2H, m), 1.67 (4H, m), 1.81 (2H, m), 3.22 (6H, m), 3.51 (3H,m), 4.22 (2H, s), 5.23 (2H, s), 7.22 (3H, m), 7.38 (3H, m), 7.55 (3H,m), 8.06 (1H, s).

Example 157S-1-(2,5-Dichlorobenzyl)-7-[4-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(47 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4B to give the title compound as a brown solid(47% yield). M.p.=180° C., LCMS: m/z=564.09 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.99 (11H, m), 2.64 (3H, m), 2.87 (1H, m), 3.48 (2H, m), 4.38(2H, s), 4.44 (1H, bs), 5.26 (2H, s), 5.44 (1H, s), 7.05 (2H, m), 7.21(1H, dd, J=8.6, 2.3 Hz), 7.37 (3H, m), 7.54 (2H, m), 8.02 (1H, s).

Example 1581-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(991 mg) was reduced as in General Procedure 3 to give the titlecompound as a brown solid (85% yield). M.p.=169° C., LCMS: m/z=421.39(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.40 (3H, m), 3.59 (2H, m), 4.39 (2H,s), 4.85 (1H, bs), 6.64 (1H, s), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd,J=8.6, 2.8 Hz), 7.35 (1H, d, J=8.6 Hz), 7.63 (1H, d, J=1.5 Hz).

Example 159S-{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone

1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazine (106mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4B to give the title compound as a brown solid(1% yield). LCMS: m/z=550.03 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.78 (4H,m), 1.99 (1H, m), 2.17 (2H, s), 2.64 (3H, m), 2.87 (1H, m), 3.48 (4H,m), 3.66 (2H, m), 4.44 (1H, m), 4.50 (2H, s), 4.92 (1H, bs), 6.64 (1H,s), 7.21 (1H, dd, J=8.5, 2.4 Hz), 7.30 (1H, d, J=2.3 Hz), 7.35 (1H, d,J=8.6 Hz), 7.39 (2H, d, J=8.3 Hz), 7.50 (2H, m), 7.61 (1H, m), 7.73 (1H,d, J=1.8 Hz).

Example 160{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazine (64mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a yellow solid(10% yield). LCMS: m/z=550.11 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.53(2H, m), 1.80 (7H, m), 2.25 (1H, m), 2.57 (4H, m), 2.98 (2H, m), 3.48(2H, t, J=4.7 Hz), 3.65 (2H, m), 3.82 (1H, bs), 4.49 (2H, s), 4.59 (1H,m), 5.00 (1H, bs), 6.63 (1H, d, J=1.3 Hz), 7.21 (1H, dd, J=8.6, 2.5 Hz),7.29 (1H, d, J=2.5 Hz), 37.38 (5H, m), 7.73 (1H, d, J=1.8 Hz).

Example 1611-(2,6-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(60 mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a brown solid(35% yield). M.p.=199° C., LCMS: m/z=564.03 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.89 (6H, m), 2.25 (1H, m), 2.59 (5H, s), 2.99 (3H, m), 3.80 (1H,bs), 4.26 (2H, d, J=1.3 Hz), 4.60 (1H, bs), 4.84 (1H, bs), 5.56 (2H, s),7.17 (1H, m), 7.33 (5H, m), 7.41 (2H, d, J=8.1 Hz), 7.94 (1H, d, J=1.8Hz),

Example 1621-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-onewas reduced as in General Procedure 3 to give the title compound as alight yellow solid. M.p.>200° C., LCMS: m/z=420.31 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 3.03 (2H, t, J=4.8 Hz), 3.42 (2H, m), 4.48 (2H, s),4.81 (1H, s), 7.09 (1H, s), 7.24 (1H, m), 7.36 (2H, d, J=8.2 Hz), 7.63(1H, d, J=1.6 Hz).

Example 163{4-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(56 mg) was reacted with(4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanoneas in General Procedure 4B to give the title compound as a yellow solid(10% yield). LCMS: m/z=470.05 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.56(3H, m), 1.90 (11H, m), 2.17 (1H, s), 2.28 (1H, m), 2.59 (5H, m), 2.98(3H, m), 3.14 (2H, t, J=4.7 Hz), 3.50 (2H, m), 3.85 (1H, bs), 4.61 (3H,s), 4.92 (1H, bs), 7.12 (1H, s), 7.23 (1H, m), 7.48 (6H, m), 7.75 (1H,d, J=1.5 Hz).

Example 164{4-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone

1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(72 mg) was reacted with(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amideas in General Procedure 4B to give the title compound as a yellow solid(22% yield). LCMS: m/z=549.94 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.83(7H, m), 2.26 (2H, m), 3.01 (5H, m), 3.57 (4H, m), 4.46 (1H, bs), 4.61(2H, s), 5.17 (1H, bs), 7.11 (1H, d, J=1.5 Hz), 7.25 (1H, m), 7.37 (2H,d, J=8.1 Hz), 7.56 (4H, m), 7.74 (1H, s).

Example 1657-(6-Chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(115 mg) was reacted with2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as inGeneral Procedure 4B to give the title compound as a yellow solid (54%yield). M.p.=205° C., LCMS: m/z=405.57 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.50 (2H, t, J=4.8 Hz), 3.67 (2H, m), 4.49 (2H, s), 5.10 (1H, bs), 6.52(1H, s), 7.21 (1H, dd, J=8.3, 2.3 Hz), 7.29 (2H, m), 7.35 (1H, d, J=8.3Hz), 7.55 (2H, m), 8.36 (1H, d, J=2.5 Hz).

Example 1661-(2,5-Dichlorobenzyl)-7-(6-pyrrolidin-1-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

Pyrrolidine (1 mL) was added to7-(6-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(49 mg), and the mixture was stirred at 87° C. for 16 hours. Thereaction mixture was then concentrated, and CH₂Cl₂ and H₂O were added.The organic phase was isolated, dried with magnesium sulfate, filteredand then purified by normal phase column chromatography eluting with 3%methanol in CH₂Cl₂ to give the title compound as a yellow solid (36%yield). M.p.>200° C., LCMS: m/z=440.19 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.99 (4H, m), 3.47 (6H, m), 3.64 (2H, t, J=4.0 Hz), 4.47 (2H, s), 4.98(1H, bs), 6.35 (1H, d, J=8.8 Hz), 6.52 (1H, d, J=1.8 Hz), 7.18 (1H, dd,J=8.3, 2.5 Hz), 7.26 (1H, m), 7.32 (1H, d, J=8.6 Hz), 7.48 (1H, dd,J=8.7, 2.4 Hz), 7.62 (1H, d, J=1.8 Hz), 8.17 (1H, d, J=2.3 Hz).

Example 1677-(2-Chloropyridin-4-yl)-1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(511 mg) was reacted with 2-chloropyridine-4-boronic acid as in GeneralProcedure 4B to give the title compound as a yellow solid (31% yield).M.p.=194° C., LCMS: m/z=405.56 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.17(2H, t, J=4.8 Hz), 3.53 (2H, m), 4.62 (2H, s), 5.12 (1H, bs), 7.06 (1H,s), 7.42 (4H, m), 7.68 (1H, m), 7.81 (1H, d, J=1.8 Hz), 8.35 (1H, d,J=5.1 Hz).

Example 168{3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamicacid tert-butyl ester

1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(40 mg) was coupled with N-boc propargylamine as in General Procedure 5to give the title compound as a yellow solid (63% yield). LCMS:m/z=447.49 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.45 (9H, s), 3.41 (2H, t,J=4.8 Hz), 3.62 (2H, s), 4.05 (2H, m), 4.40 (2H, s), 4.81 (1H, m), 5.41(1H, bs), 6.41 (1H, s), 7.21 (2H, m), 7.34 (1H, d, J=8.3 Hz), 7.61 (1H,s).

Example 1693-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine

{3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamicacid tert-butyl ester (19 mg), trifluoroacetic acid (250 μL) and CH₂Cl₂(1 mL) were stirred under nitrogen at room temperature for 1.5 hours. 2N NaOH (2 mL) and CH₂Cl₂ (approx. 10 mL) were added. The organic phasewas isolated, washed twice with H₂O, washed once with brine, dried oversodium sulfate, filtered and then purified by normal phase columnchromatography, eluting with 5% methanol in methylene chloride, to givethe title compound as an off-white solid (37% yield). M.p.=183° C.,LCMS: m/z=347.35 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.42 (2H, t, J=4.8Hz), 3.61 (4H, m), 4.41 (2H, s), 5.04 (1H, bs), 6.42 (1H, s), 7.21 (2H,m), 7.34 (1H, d, J=8.3 Hz), 7.59 (1H, s, J=1.0 Hz).

Example 170{3-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamicacid tert-butyl ester

1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(1.951 g) was coupled with N-boc propargylamine as in General Procedure5 to give the title compound as an orange solid. LCMS: m/z=447.53(M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.40 (9H, s), 2.86 (2H, m), 3.27(2H, m), 3.95 (2H, d, J=5.6 Hz), 4.46 (2H, s), 6.86 (1H, s), 6.89 (1H,s), 7.29 (1H, m), 7.42 (2H, m), 7.54 (2H, d, J=8.3 Hz).

Example 1713-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine,trifluoroacetic acid salt

{3-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamicacid tert-butyl ester (641 mg), trifluoroacetic acid (3.1 mL) and CH₂Cl₂(31 mL) were stirred overnight under nitrogen at room temperature, thenconcentrated to give the title compound.

Example 172N-{3-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}-2-dimethylamino-acetamide

3-[1-(2,6-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine,trifluoroacetic acid salt(s) (99 mg) and 1 N NaOH (4 mL) were stirred atroom temperature for two (2) hours. The reaction mixture was thenconcentrated, anhydrous CH₂Cl₂ (4 mL), dimethylaminoacetyl chloride HCl(48 mg) and triethylamine (45 μL) were added, and the reaction wasstirred at room temperature for 16 hours. The reaction mixture was thenconcentrated and purified with normal phase column chromatography,eluting with 9/1 CH₂Cl₂/methanol to 97/3/1 CH₂Cl₂/methanol/NH₄OH to givethe title compound as a yellow solid. M.p.>200° C., LCMS: m/z=432.04(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.31 (6H, s), 3.00 (4H, m), 3.44 (2H,m), 4.31 (2H, d, J=5.6 Hz), 4.50 (2H, s), 5.11 (1H, bs), 6.93 (1H, d,J=1.0 Hz), 7.23 (1H, m), 7.37 (2H, m), 7.63 (1H, d, J=1.5 Hz).

Example 173{3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}-dimethylamine

1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(113 mg) was coupled with 1-dimethylamino-2-propyne as in GeneralProcedure 5 to give the title compound as a yellow solid (49% yield).M.p.=168° C., LCMS: m/z=375.08 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.31(6H, s), 3.38 (4H, m), 3.61 (2H, t, J=4.0 Hz), 4.40 (2H, s), 5.54 (1H,bs), 6.45 (1H, d, J=1.5 Hz), 7.21 (2H, m), 7.33 (1H, m), 7.61 (1H, d,J=1.5 Hz).

Example 1741-(2,5-Dichlorobenzyl)-7-[3-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)prop-1-ynyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(108 mg) was coupled with 4-prop-2-ynyl-thiomorpholine 1,1-dioxide as inGeneral Procedure 5 to give the title compound as an off-white solid(34% yield). M.p.>200° C., LCMS: m/z=467.33 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 3.11 (8H, s), 3.40 (2H, t, J=4.8 Hz), 3.56 (2H, s), 3.61 (2H, t,J=4.7 Hz), 4.41 (2H, s), 6.42 (1H, dt, J=1.5 Hz), 7.22 (2H, m), 7.35(1H, d, J=8.3 Hz), 7.58 (1H, d, J=1.5 Hz).

Example 1751-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (2.935 g) was treatedwith 2-(1-bromoethyl)-3-chloro-1,4-difluorobenzene (Preparation 3) as inGeneral Procedure 1 to give the title compound as an orange solid (11%yield). LCMS: m/z=449.86 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.79 (3H,m), 2.73 (1H, s), 2.89 (1H, s), 5.76 (1H, m), 6.96 (1H, s), 7.29 (1H,m), 7.43 (1H, m), 7.62 (1H, s), 7.83 (1H, m).

Example 1761-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(514 mg) was reduced as in General Procedure 3 to give the titlecompound as an orange solid (59% yield). M.p.=166° C., LCMS: m/z=436.07(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.63 (3H, m), 3.46 (4H, m), 4.75 (1H,bs), 5.16 (1H, quartet, J=7.2 Hz), 6.81 (1H, s), 6.97 (1H, m), 7.08 (1H,m), 7.54 (1H, d, J=1.5 Hz).

Example 1771-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(53 mg) was coupled to1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4B to give the title compound as an orange solid(15% yield). LCMS: m/z=435.02 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.66(3H, d, J=7.1 Hz), 2.35 (3H, s), 2.54 (4H, t, J=4.9 Hz), 3.54 (8H, m),4.89 (1H, bs), 5.31 (1H, m), 6.68 (1H, d, J=8.9 Hz), 6.72 (1H, s), 6.96(1H, m), 7.05 (1H, m), 7.52 (1H, dd, J=8.8, 2.5 Hz), 7.57 (1H, s), 8.29(1H, d, J=2.3 Hz).

Example 1781-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.051 g) was alkylatedwith 3-fluoro-2-(trifluoromethyl)benzyl bromide as in General Procedure1 to give the title compound as a light brown solid (54% yield).M.p.>200° C., LCMS: m/z=451.79 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.17(2H, s), 5.20 (2H, bs), 7.01 (1H, d, J=7.6 Hz), 7.17 (1H, s), 7.23 (1H,s), 7.42 (1H, m), 7.63 (1H, m), 7.86 (1H, m).

Example 1791-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(922 mg) was reduced as in General Procedure 3 to give the titlecompound as a brown solid (64% yield). LCMS: m/z=437.80 (M+H⁺), ¹H-NMR(DMSO-d₆, 400 MHz) δ 3.28 (2H, m), 3.40 (2H, m), 4.60 (2H, s), 4.68 (1H,m), 6.59 (1H, d, J=1.3 Hz), 6.70 (1H, s), 7.22 (1H, d, J=7.8 Hz), 7.43(1H, d, J=1.5 Hz), 7.69 (1H, m).

Example 1801-(2,5-Dichlorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(94 mg) was coupled to1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4B to give the title compound as a brown solid(50% yield). LCMS: m/z=468.97 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.33(3H, s), 2.51 (4H, t, J=5.1 Hz), 3.48 (2H, m), 3.55 (4H, t, J=5.1 Hz),3.64 (2H, t, J=4.7 Hz), 4.46 (2H, s), 5.20 (1H, bs), 6.52 (1H, d, J=1.5Hz), 6.65 (1H, d, J=8.8 Hz), 7.19 (1H, dd, J=8.5, 2.4 Hz), 7.26 (1H, d,J=2.3 Hz), 7.33 (1H, d, J=8.3 Hz), 7.52 (1H, dd, J=8.6, 2.5 Hz), 7.62(1H, d, J=1.5 Hz), 8.20 (1H, d, J=2.5 Hz).

Example 1811-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(101 mg) was coupled to1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4B to give the title compound as a yellow solid(31% yield). LCMS: m/z=487.09 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.33(3H, s), 2.51 (4H, t, J=4.9 Hz), 3.49 (2H, m), 3.55 (4H, t, J=4.9 Hz),3.63 (2H, m), 4.65 (2H, s), 5.08 (1H, bs), 6.48 (1H, d, J=1.8 Hz), 6.64(1H, d, J=8.8 Hz), 7.09 (1H, m), 7.26 (1H, m), 7.45 (2H, m), 7.62 (1H,d, J=1.8 Hz), 8.18 (1H, d, J=2.5 Hz).

Example 1821-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(308 mg) was coupled to2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as inGeneral Procedure 4B to give the title compound (50% yield). LCMS:m/z=407.32 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.30 (2H, t, J=4.8 Hz),3.56 (2H, m), 4.34 (2H, s), 5.35 (1H, bs), 7.06 (2H, m), 7.15 (1H, m),7.33 (1H, dd, J=5.3, 1.5 Hz), 5.46 (1H, m), 7.80 (1H, d, J=1.5 Hz), 8.34(1H, d, J=5.3 Hz).

Example 1831-(2-Chloro-3,6-difluorobenzyl)-7-(2-pyrrolidin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

Pyrrolidine (1 mL) was added to1-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(32 mg). The reaction mixture was stirred at 87° C. for 72 hours andthen concentrated. The residue was purified by normal phase columnchromatography eluting with 5% methanol in CH₂Cl₂ to give the titlecompound as a yellow solid (35% yield). LCMS: m/z=442.21 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 2.03 (4H, m), 3.33 (2H, m), 3.53 (6H, m), 4.53 (2H,d, J=1.3 Hz), 5.06 (1H, bs), 6.43 (1H, d, J=0.8 Hz), 6.68 (1H, dd,J=5.4, 1.4 Hz), 7.02 (1H, m), 7.12 (2H, m), 7.79 (1H, d, J=1.8 Hz), 8.15(1H, d, J=5.6 Hz).

Example 1845-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2-ylamine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(87 mg) was coupled to5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-ylamine as inGeneral Procedure 4B to give the title compound as a light brown solid(52% yield). M.p.>200° C., LCMS: m/z=388.10 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 3.28 (2H, m), 3.51 (2H, m), 4.52 (2H, d, J=1.3 Hz), 6.58 (1H, dd,J=8.6, 0.8 Hz), 7.00 (1H, d, J=2.0 Hz), 7.05 (1H, m), 7.14 (1H, m), 7.30(2H, s), 7.54 (1H, d, J=2.0 Hz), 7.58 (1H, dd, J=8.6, 2.5 Hz), 8.13 (1H,dd, J=2.4, 0.6 Hz).

Example 1851-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(88 mg) was coupled to1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4B to give the title compound as a light brownsolid (16% yield). M.p.=219° C., LCMS: m/z=471.12 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.36 (3H, s), 2.54 (4H, t, J=5.1 Hz), 3.27 (2H, t, J=4.8 Hz),3.51 (2H, t, J=4.7 Hz), 3.59 (4H, t, J=5.1 Hz), 4.50 (2H, d, J=1.0 Hz),5.01 (1H, bs), 6.70 (1H, d, J=8.8 Hz), 7.03 (2H, m), 7.11 (1H, m), 7.61(1H, dd, J=8.8, 2.5 Hz), 7.64 (1H, d, J=1.8 Hz), 8.35 (1H, d, J=2.3 Hz).

Example 1861-(2-Chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

Morpholine (2 mL) was added to1-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(61 mg), and the mixture was heated in a microwave oven for two (2)hours at 180° C. The mixture was then concentrated, and the residue waspurified through silica gel chromatography followed by preparativereversed-phase HPLC. The trifluoroacetic acid salt was neutralized withsaturated sodium bicarbonate, and the free base extracted into methylenechloride, washed with brine and dried with magnesium sulfate. Thesolution was concentrated to give the title compound as a yellow solid(21% yield). M.p.=157° C., LCMS: m/z=458.07 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 3.38 (2H, t, J=4.7 Hz), 3.56 (4H, t, J=4.8 Hz), 3.62 (2H, t,J=4.5 Hz), 3.86 (4H, t, J=4.8 Hz), 4.58 (2H, s), 6.65 (1H, s), 6.76 (1H,d, J=5.1 Hz), 7.06 (2H, m), 7.16 (1H, m), 7.59 (2H, m), 8.22 (1H, d,J=5.1 Hz).

Example 1871-(2,5-Dichlorobenzyl)-7-iodo-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

To a solution of1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(305 mg) in anhydrous N,N-dimethylformamide was added NaH (1.6 eq)followed by iodomethane (1.4 eq). The reaction mixture was stirred atroom temperature for 48 hours and then concentrated. Columnchromatography gave the title compound as a yellow solid (56% yield).LCMS: m/z=434.17 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.09 (3H, s), 3.42(2H, m), 3.48 (2H, m), 4.36 (2H, s), 6.54 (1H, d, J=1.8 Hz), 7.17 (1H,d, J=2.3 Hz), 7.21 (1H, dd, J=8.6, 2.5 Hz), 7.34 (1H, d, J=4.3 Hz), 7.72(1H, d, J=1.8 Hz).

Example 1881-(2,5-Dichlorobenzyl)-4-methyl-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2,5-Dichlorobenzyl)-7-iodo-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(83 mg) was coupled to1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4B to give the title compound as a brown solid(43% yield). LCMS: m/z=483.33 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.33(3H, s), 2.52 (4H, t, J=5.1 Hz), 3.16 (3H, s), 3.53 (8H, m), 4.45 (2H,s), 6.45 (1H, d, J=1.8 Hz), 6.65 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=8.5,4.8 Hz), 7.25 (1H, d, J=2.3 Hz), 7.32 (1H, d, J=8.3 Hz), 7.52 (1H, dd,J=8.6, 2.5 Hz), 7.75 (1H, d, J=1.8 Hz), 8.22 (1H, d, J=2.5 Hz).

Example 1891-(2-Chloro-3,6-difluorobenzyl)-7-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(100 mg) was coupled to4-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-morpholine asin General Procedure 4B to give the title compound as a yellow solid.LCMS: m/z=457.05 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.21 (4H, t, J=4.8Hz), 3.29 (2H, t, J=4.7 Hz), 3.52 (2H, t, J=4.2 Hz), 3.89 (4H, t, J=4.8Hz), 4.52 (2H, s), 5.09 (1H, bs), 6.84 (1H, dd, J=8.0, 1.9 Hz), 7.00(3H, m), 7.10 (2H, m), 7.29 (1H, m), 7.72 (1H, d, J=1.8 Hz).

Example 1901-(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(88 mg) was coupled to1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4B to give the title compound as a light yellowsolid (15% yield). LCMS: m/z=471.07 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ2.36 (3H, s), 2.56 (4H, t, J=4.9 Hz), 3.33 (2H, t, J=4.7 Hz), 3.55 (2H,m), 3.62 (4H, t, J=4.9 Hz), 4.53 (2H, s), 5.23 (1H, bs), 6.72 (1H, s),6.78 (1H, dd, J=5.3, 1.3 Hz), 7.03 (2H, m), 7.12 (1H, m), 7.77 (1H, d,J=1.8 Hz), 8.18 (1H, d, J=5.1 Hz).

Example 1911-(2-Chloro-3,6-difluorobenzyl)-7-[1-(3-methylbutyl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(99 mg) was reacted with 1-(3-methylbutyl)-1H-pyrazole-4-boronic acid,pinacol ester as in General Procedure 4B to give the title compound as abrown solid (21% yield). M.p.=134° C., LCMS: m/z=431.92 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 0.96 (6H, d, J=6.6 Hz), 1.61 (1H, m), 1.80 (2H, m),3.28 (2H, t, J=4.8 Hz), 3.51 (2H, m), 4.15 (2H, t, J=7.5 Hz), 4.50 (2H,s), 4.90 (1H, bs), 6.96 (1H, d, J=1.5 Hz), 7.02 (1H, m), 7.12 (1H, m),7.51 (1H, s), 7.63 (2H, m).

Example 1921-(2-Chloro-3,6-difluorobenzyl)-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[(2-Chloro-3,6-difluoro)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(224 mg) was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylicacid-tert-butyl ester as in General Procedure 4B to give the titlecompound as an off-white solid. m.p.=272° C., LCMS: m/z=361.78 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 3.30 (2H, t, J=4.7 Hz), 3.41 (1H, m), 3.50(2H, m), 4.51 (2H, s), 7.00 (1H, d, J=1.5 Hz), 7.04 (1H, m), 7.13 (1H,m), 7.59 (1H, d, J=1.5 Hz), 7.72 (2H, s).

Example 1934-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester

1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(7.0 g) was reacted with 4-ethoxycarbonyl phenyl boronic acid as inGeneral Procedure 4A. The title compound was obtained as a yellow solid(71% yield). M.p.=154° C., LCMS: m/z=476.04 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.40, (t, 3H), 3.49 (m, 2H), 3.71 (m, 2H), 4.35 (q, 2H), 4.61 (s,2H), 5.72 (bs, 1H), 6.62 (s, 1H), 7.44 (m, 3H), 7.50 (s, 1H), 7.63 (d,1H), 7.72 (s, 1H), 8.07 (d, 2H).

Example 1943-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester

1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(7.5 g) was reacted with 3-ethoxycarbonyl phenyl boronic acid as inGeneral Procedure 4A. The title compound was obtained as a white solid(72% yield). m.p.=174° C., LCMS: m/z=475.95 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.40 (t, 3H), 3.48 (m, 2H), 3.69 (m, 2H), 4.32 (q, 2H), 4.63 (s,2H), 5.51 (bs, 1H), 6.52 (s, 1H), 7.35 (m, 1H), 7.42 (m, 1H), 7.48 (s,1H), 7.54 (m, 1H), 7.65 (d, 1H), 7.70 (s, 1H), 7.90 (d, 1H), 8.03 (s,1H).

Example 1954-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid

4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester (5.1 g) was saponified as in General Procedure 7 togive the title compound as a light orange solid (88% yield). LCMS:m/z=447.88 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.41 (m, 2H), 3.60 (m,2H), 4.80 (s, 2H), 7.07 (s, 1H), 7.63 (m, 3H), 7.74 (s, 1H), 7.82 (d,1H), 7.95 (m, 2H), 8.81 (s, 1H), 13.01 (bs, 1H).

Example 1963-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid

3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester (5.5 g) was saponified as in General Procedure 7 togive the title compound as a tan solid (97% yield). LCMS: m/z=448.07(M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.42 (m, 2H), 3.51 (m, 2H), 4.62 (s,2H), 6.61 (s, 1H), 6.75 (s, 1H), 7.35 (m, 2H), 7.52 (m, 3H), 7.62 (s,1H), 7.74 (d, 1H), 7.82 (d, 1H), 7.88 (s, 1H).

Example 197(2-{4-[1-(2-Chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyrazol-1-yl}ethyl)dimethylamine

Anhydrous DMF (2 mL) was added to a mixture of1-(2-chloro-3,6-difluorobenzyl)-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine(57 mg, 0.000158 mol), cesium carbonate (0.110 g) and2-dimethylaminoethyl chloride HCl (0.025 g). The reaction mixture wasstirred at room temperature under nitrogen for 13 days and thenconcentrated and dissolved in methylene chloride. The organic phase waswashed with water, dried with magnesium sulfate, filtered, andconcentrated. The residue was purified on normal phase silica gelchromatography to give the title compound as an off-white solid (9%yield). LCMS: m/z=433.13 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.30 (6H, s),2.79 (2H, t, J=6.8 Hz), 3.29 (2H, t, J=4.7 Hz), 3.51 (2H, m), 4.24 (2H,t, J=6.8 Hz), 4.50 (2H, s), 4.77 (1H, bs), 6.97 (1H, s), 7.02 (1H, m),7.12 (1H, m), 7.60 (1H, s), 7.63 (1H, d, J=1.5 Hz), 7.66 (1H, s).

Example 1981-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine

1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine(293 mg) was reacted with 2-(piperazin-1-yl)pyridine-4-boronic acid,pinacol ester as in General Procedure 4B to give the title compound asan off-white solid. m.p.=189° C., LCMS: m/z=489.08 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 2.98 (4H, m), 3.49 (6H, m), 3.71 (2H, m), 4.61 (2H,s), 5.29 (1H, s), 5.34 (1H, bs), 6.55 (2H, m), 6.64 (1H, dd, J=5.2, 1.4Hz), 7.36 (1H, d, J=8.1 Hz), 7.52 (1H, s), 7.64 (1H, d, J=8.3 Hz), 7.77(1H, d, J=2.0 Hz), 8.12 (1H, d, J=5.3 Hz).

Example 1991-[4-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}pyridin-2-yl)piperazin-1-yl]ethanone

To a solution of1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine(63 mg, 0.000129 mol) in anhydrous DMF (1 mL) was added acetyl chloride(0.012 mL) and triethylamine (0.020 mL). The mixture was stirred at roomtemperature under nitrogen overnight and then concentrated. The residuewas purified on normal phase silica gel chromatography to give the titlecompound as a yellow solid (56% yield). m.p.=241° C., LCMS: m/z=531.31(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.15 (3H, s), 3.47 (2H, m), 3.52 (2H,m), 3.57 (2H, m), 3.62 (2H, m), 3.73 (4H, m), 4.61 (2H, s), 5.25 (1H,bs), 6.55 (2H, m), 6.69 (1H, d, J=5.3 Hz), 7.37 (1H, d, J=8.3 Hz), 7.52(1H, s), 7.65 (1H, d, J=8.3 Hz), 7.78 (1H, bs), 8.12 (1H, d, J=5.3 Hz).

Example 2001-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine

1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine(109 mg) was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylicacid-tert-butyl ester as in General Procedure 4B, then added 6 mL CH₂Cl₂and TFA (0.6 mL), and purified on normal phase silica gel chromatographyto give the title compound as an off-white solid (44% yield). m.p.=271°C., LCMS: m/z=394.24 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.50 (2H, m),3.66 (2H, m), 4.05 (3H, s), 4.61 (2H, s), 6.50 (1H, d, J=1.5 Hz), 7.40(1H, s), 7.50 (1H, s), 7.56 (3H, m), 7.68 (1H, d, J=8.6 Hz).

Example 2011-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine(111 mg) was reacted with 1-(triisopropylsilyl)-1H-pyrrole-3-boronicacid as in General Procedure 4B to give the title compound as anoff-white solid (80% yield). LCMS: m/z=349.34 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 1.08 (18H, d, J=7.6 Hz), 1.41 (3H, m), 3.49 (2H, m), 3.65 (2H,m), 4.58 (2H, s), 4.92 (1H, bs), 6.37 (1H, m), 6.54 (1H, d, J=1.8 Hz),6.72 (1H, m), 6.76 (1H, m), 7.32 (1H, d, J=8.6 Hz), 7.54 (1H, s), 7.61(1H, d, J=8.6 Hz), 7.70 (1H, m).

Example 2021-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine

Anhydrous tetrahydrofuran (1 mL) and tetrabutylammonium fluoride, 1 Msolution in tetrahydrofuran (0.761 mL) were added to1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine(107 mg, 0.000195 mol). The reaction was stirred at room temperatureunder nitrogen for two (2) hours and then concentrated. The residue waspurified on normal phase silica gel chromatography to give the titlecompound as an off-white solid. LCMS: m/z=393.24 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 3.35 (2H, bs), 3.48 (2H, m), 3.63 (2H, m), 4.59 (2H, s), 6.26(1H, s), 6.56 (1H, d, J=1.3 Hz), 6.74 (1H, t, J=2.0 Hz), 6.82 (1H, s),7.34 (1H, d, J=8.3 Hz), 7.50 (1H, s), 7.60 (1H, s), 7.64 (1H, d, J=8.3Hz).

Example 2031-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(112 mg) was reacted with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asin General Procedure 4B to give the title compound as a brown solid (74%yield). m.p.=156° C., LCMS: m/z=408.25 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.48 (2H, m), 3.65 (2H, m), 3.87 (3H, s), 4.58 (2H, s), 5.06 (1H, s),6.45 (1H, s), 7.36 (2H, m), 7.49 (2H, m), 7.63 (2H, m).

Example 204{1-[(5-Chloro-2-trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}piperidin-1-yl-methanone

4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid (89 mg) was reacted with piperidine as in General Procedure 8 togive the title compound as an orange solid (64% yield). m.p.=216° C.,LCMS: m/z=515.27 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.61 (6H, m), 2.88(1H, s), 2.95 (1H, s), 3.38 (2H, s), 3.49 (2H, m), 3.69 (2H, m), 4.62(2H, s), 5.26 (1H, s), 6.60 (1H, s), 7.37 (5H, m), 7.51 (1H, s), 7.64(1H, d, J=8.3 Hz), 7.75 (1H, d, J=1.5 Hz).

Example 205{1-[(5-Chloro-2-trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-(4-methoxy-piperidin-1-yl)methanone

4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid (80 mg) was reacted with 4-methoxypiperidine HCl as in GeneralProcedure 8 to give the title compound as an orange solid (58% yield).LCMS: m/z=545.26 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.73 (4H, m), 2.88(1H, s), 2.95 (1H, s), 3.36 (3H, s), 3.47 (4H, m), 3.68 (3H, m), 4.62(2H, s), 5.35 (1H, bs), 6.59 (1H, d, J=1.3 Hz), 7.38 (5H, m), 7.51 (1H,s), 7.64 (1H, d, J=8.3 Hz), 7.75 (1H, s).

Example 206[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperazin-1-yl)-methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-phenylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=481.97 (M+H⁺); retention time=1.12minutes.

Example 207[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-pyrimidin-2-yl-piperazin-1-yl)-methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(2-pyrimidyl)piperazine as in General Procedure10 to give the title compound. LCMS: m/z=483.93 (M+H⁺); retentiontime=0.99 minutes.

Example 208[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=530.89(M+H⁺); retention time=1.1 minutes.

Example 2091-{1-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperidin-4-yl}-1,3-dihydrobenzoimidazol-2-one

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1,3-dihydrobenzoimidazol-2-one as in GeneralProcedure 10 to give the title compound. LCMS: m/z=536.96 (M+H⁺);retention time=0.97 minutes.

Example 210[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-methoxyphenyl)piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(2-methoxyphenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=511.94 (M+H⁺);retention time=1.09 minutes.

Example 211[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-[3-(trifluoromethyl)phenyl]piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=549.92(M+H⁺); retention time=1.24 minutes.

Example 212[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperidin-1-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-phenylpiperidine as in General Procedure 10 togive the title compound. LCMS: m/z=480.99 (M+H⁺); retention time=1.17minutes.

Example 213[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(3,4-dichlorophenyl)-piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(3,4-dichlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=549.85 (M+H⁺);retention time=1.31 minutes.

Example 214(4-Benzhydrylpiperazin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-benzhydrylpiperazine as in General Procedure 10to give the title compound. LCMS: m/z=571.95 (M+H⁺); retention time=1.2minutes.

Example 215(4-Benzylpiperidin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-benzylpiperidine as in General Procedure 10 togive the title compound. LCMS: m/z=495.02 (M+H⁺); retention time=1.25minutes.

Example 2168-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as inGeneral Procedure 10 to give the title compound. LCMS: m/z=550.97(M+H⁺); retention time=1.02 minutes.

Example 217[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(thieno[3,2-d]pyrimidin-4-yl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=539.89(M+H⁺); retention time=0.81 minutes.

Example 218[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4-methoxybenzyl)piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(4-methoxybenzyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=525.95 (M+H⁺);retention time=0.81 minutes.

Example 219(4-Benzoylpiperazin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-benzoylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=509.83 (M+H⁺); retention time=0.97minutes.

Example 220[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(fiuro[3,2-c]pyridin-4-yl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=522.95(M+H⁺); retention time=0.82 minutes.

Example 221[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as inGeneral Procedure 10 to give the title compound. LCMS: fi/z=539.95(M+H⁺); retention time=1.15 minutes.

Example 222[4-(3-Chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(3-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=515.91 (M+H⁺);retention time=1.21 minutes.

Example 2231-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-pyridin-2-yl-ethyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-(2-pyridyl)ethylamine as in General Procedure 10to give the title compound. LCMS: m/z=441.87 (M+H⁺); retention time=0.77minutes.

Example 2244-{[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]amino}piperidine-1-carboxylicacid ethyl ester

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with ethyl 4-amino-1-piperidinecarboxylate as inGeneral Procedure 10 to give the title compound. LCMS: m/z=491.94(M+H⁺); retention time=1.02 minutes.

Example 2251-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (1-benzyl-piperidin-4-yl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-amino-1-benzylpiperidine as in General Procedure10 to give the title compound. LCMS: m/z=509.99 (M+H⁺); retentiontime=0.82 minutes.

Example 2261-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2,2-diphenylethyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2,2-diphenylethylamine as in General Procedure 10to give the title compound. LCMS: m/z=516.96 (M+H⁺); retention time=1.23minutes.

Example 2271-{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin-1-yl}ethanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-acetylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=447.97 (M+H⁺); retention time=0.84minutes.

Example 2281-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 3-chlorobenzylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 3-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=460.9 (M+H⁺); retention time=1.14minutes.

Example 229[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(2-(2-pyridyl)ethyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=510.96 (M+H⁺);retention time=0.72 minutes.

Example 2301-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 4-(trifluoromethoxy)benzylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-(trifluoromethoxy)benzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=510.89 (M+H⁺);retention time=1.21 minutes.

Example 231[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-morpholin-4-yl-piperidin-1-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-morpholin-4-yl-piperidine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=489.99 (M+H⁺);retention time=0.68 minutes.

Example 2321-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-thiophen-2-yl-ethyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-(2-thiophenyl)ethylamine as in General Procedure10 to give the title compound. LCMS: m/z=446.92 (M+H⁺); retentiontime=1.08 minutes.

Example 2331-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid benzhydrylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with benzhydrylamine as in General Procedure 10 to givethe title compound. LCMS: m/z=502.95 (M+H⁺); retention time=1.23minutes.

Example 2341-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (pyridin-4-ylmethyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with (4-pyridyl)methylamine as in General Procedure 10to give the title compound. LCMS: m/z=427.98 (M+H⁺); retention time=0.73minutes.

Example 2351-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (pyridin-3-ylmethyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with (3-pyridyl)methylamine as in General Procedure 10to give the title compound. LCMS: m/z=427.98 (M+H⁺); retention time=0.76minutes.

Example 2362-{4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin-1-yl}-N-isopropylacetamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with N-isopropyl-1-piperazineacetamide as in GeneralProcedure 10 to give the title compound. LCMS: m/z=504.97 (M+H⁺);retention time=0.78 minutes.

Example 237[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(2-methylquinolin-4-yl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=546.97 (M+H⁺);retention time=0.8 minutes.

Example 238[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with (S)-1-(2-pyrrolidinylmethyl)pyrrolidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=474.04(M+H⁺); retention time=0.76 minutes.

Example 2391-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 3,5-bis-(trifluoromethyl)benzylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=562.86 (M+H⁺);retention time=1.32 minutes.

Example 2401-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid [2-(4-sulfamoylphenyl)ethyl]amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=519.88 (M+H⁺);retention time=0.94 minutes.

Example 241[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2,3,5,6-tetrahydro-[1,2′]bipyrazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=483.94 (M+H⁺);retention time=0.94 minutes.

Example 2421-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-phenylthiazol-4-yl-methyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-(aminomethyl)-2-phenylthiazole as in GeneralProcedure 10 to give the title compound. LCMS: m/z=509.91 (M+H⁺);retention time=1.17 minutes.

Example 243[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]morpholin-4-yl-methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with morpholine as in General Procedure 10 to give thetitle compound. LCMS: m/z=407.01 (M+H⁺); retention time=0.9 minutes.

Example 2441-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (naphthalen-1-yl-methyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(aminomethyl)naphthalene as in General Procedure10 to give the title compound. LCMS: m/z=476.96 (M+H⁺); retentiontime=1.17 minutes.

Example 2451-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid indan-1-ylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-aminoindan as in General Procedure 10 to givethe title compound. LCMS: m/z=452.99 (M+H⁺); retention time=1.14minutes.

Example 2461-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid benzylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with benzylamine as in General Procedure 10 to give thetitle compound. LCMS: m/z=427.01 (M+H⁺); retention time=1.07 minutes.

Example 247[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4-methoxyphenyl)piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(4-methoxyphenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=511.94 (M+H⁺);retention time=1.07 minutes.

Example 2481-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid cyclohexylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with cyclohexylamine as in General Procedure 10 to givethe title compound. LCMS: m/z=419.07 (M+H⁺); retention time=1.11minutes.

Example 2491-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (biphenyl-4-ylmethyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-phenylbenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=502.95 (M+H⁺); retention time=1.25minutes.

Example 250[4-(4-Chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(4-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=515.91 (M+H⁺);retention time=1.21 minutes.

Example 2511-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-phenoxyethyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-phenoxyethylamine as in General Procedure 10 togive the title compound. LCMS: m/z=456.96 (M+H⁺); retention time=1.11minutes.

Example 252[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-(2-tetrahydrofuranylcarbonyl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=503.96(M+H⁺); retention time=0.88 minutes.

Example 2531-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid phenethyl-amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with phenethylamine as in General Procedure 10 to givethe title compound. LCMS: In/z=441.01 (M+H⁺); retention time=1.111minutes.

Example 2541-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (tetrahydrofuran-2-yl-methyl)amide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-tetrahydrofuranylmethylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=421.02 (M+H⁺);retention time=0.95 minutes.

Example 255[4-(4-Chlorobenzyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(4-chlorobenzyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=529.92 (M+H⁺);retention time=0.9 minutes.

Example 2561-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 2-chloro-benzylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=460.93 (M+H⁺); retention time=1.14minutes.

Example 257[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-(trifluoromethyl)phenyl)piperazin-1-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(2-(trifluoromethyl)phenyl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=549.92(M+H⁺); retention time=1.24 minutes.

Example 2581-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 4-methoxybenzylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-methoxybenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=456.96 (M+H⁺); retention time=1.08minutes.

Example 2591-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid indan-2-ylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-aminoindan as in General Procedure 10 to givethe title compound. LCMS: m/z=452.99 (M+H⁺); retention time=1.13minutes.

Example 260[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenethyl-piperazin-1-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(2-phenethyl)piperazine as in General Procedure10 to give the title compound. LCMS: m/z=509.99 (M+H⁺); retentiontime=0.84 minutes.

Example 261[4-(2-Chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(2-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=515.91 (M+H⁺);retention time=1.21 minutes.

Example 262[(4-Cyclohexylmethyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 1-(cyclohexylmethyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=502.04 (M+H⁺);retention time=0.85 minutes.

Example 2631-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 4-sulfamoyl-benzylamide

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10to give the title compound. LCMS: m/z=505.87 (M+H⁺); retention time=0.93minutes.

Example 264[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2-pyridin-3-yl-pyrrolidin-1-yl)methanone

[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure10 to give the title compound. LCMS: m/z=467.97 (M+H⁺); retentiontime=0.82 minutes.

Example 265 3-(6-bromo-pyridin-2-ylamino)propionic acid

2-Amino-6-bromopyridine (25.0 g) was added to a mixture of ethylacrylate (17.39 g) (1.2 eq) and acetic acid (4.55 g, 0.52 eq). Thereaction mixture was heated at 130° C. for 70 hours and then cooled toroom temperature. An aqueous NaOH solution (6N, 60 mL, 2.50 eq) wasadded and the resulting mixture was heated at reflux for one (1) hourand then cooled to room temperature. The solution was washed twice withether and then acidified to pH 4-5 with concentrated HCl. Theprecipitate was collected by filtration to give the title compound as atan solid (68% yield). M.p. 108-109° C., LCMS: m/z=245.06 (M+H⁺), ¹H-NMR(DMSO-d₆, 400 MHz) δ 3.33-3.40 (m, 4H), 6.46 (d, J=8.2 Hz, 1H), 6.63 (d,J=7.3 Hz, 1H), 7.02 (t, J=5.4 Hz, 1H), 7.27 (dd, J=8.2 and 7.3 Hz, 1H),12.22 (bs, 1H).

Example 266 7-bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one

3-(6-Bromo-pyridin-2-ylamino)propionic acid (5.0 g) was combined withEaton's reagent (100 mL) in a ratio of 5 g3-(6-bromo-pyridin-2-ylamino)propionic acid per 100 mL Eaton's reagent.The resulting mixture was heated at 75° C. for 2.5 hours. Ice cold water(50 mL) was added to the reaction mixture, followed by aqueous NaOH (50%w/w) to pH 12. The mixture was then extracted twice with ethyl acetate(200 mL) and the combined organic phases were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The mixture waspurified by silica gel chromatography using a gradient of 0-80% ethylacetate/hexane as the eluting solvent to give the title compound as ayellow solid (34% yield). M.p. 196-197° C., LCMS: m/z=227.26 (M+H⁺),¹H-NMR (DMSO-d₆, 400 MHz) δ 2.57 (t, J=7.2 Hz, 2H), 3.34-3.49 (m, 2H),6.80 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.96 (bs, 1H).

Example 267 7-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol

7-Bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one (1.459 g) was placed inmethanol (25 mL) and sodium borohydride (437 mg, 1.84 eq) was addedportionwise over five (5) minutes. The reaction was stirred at roomtemperature for 15 minutes and then quenched with acetic acid (3 mL).The reaction mixture was concentrated under reduced pressure and theresidue was taken up in toluene (100 mL). Silica gel was added and themixture was concentrated under reduced pressure. Purification by silicagel chromatography using dry loading and a gradient of 0-80% ethylacetate/hexane as the eluting solvent gave the title compound as a paleyellow solid (78% yield). M.p. 130-131° C., LCMS: m/z=230.71 (M+H⁺),¹H-NMR (MeOH-d₄, 400 MHz) δ 1.80-1.94 (m, 2H), 3.33-3.48 (m, 2H), 4.66(t, J=4.4 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H).

Example 268 6-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol

7-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (460 mg) was dissolvedin anhydrous tetrahydrofuran (25 mL) and cooled to −78° C. A solution ofn-butyllithium in tetrahydrofuran was added (1.6 M, 8.5 mL) (5-7 equiv.)and the reaction was warmed slowly to room temperature. After 2-5 hours,methanol (2 mL) was added and the contents were concentrated to dryness.The residue was dissolved in a mixture of dichloromethane and aceticacid (1:1, v/v, 20 mL) and N-bromosuccinimide (450 mg) (1.2 equiv.) wereadded. After 45 minutes, the mixture was concentrated to dryness ontosilica gel, and purified by silica gel chromatography to give the titlecompound as yellow solids (25-65% yield). M.p. 125-128° C., LCMS:m/z=229 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.72 (m, 2H), 3.25 (m, 2H),4.56 (m, 1H), 5.33 (d, J=5.0 Hz, 1H), 6.8 (bs, 1H), 7.47 (d, J=2.5 Hz,1H), 7.87 (d, J=2.5 Hz, 1H).

Example 2696-[6-(4-Methyl-piperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol

6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (89 mg) was reactedwith1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine(125 mg) as in General Procedure 13. Silica gel chromatography using agradient of 0-10% (5% NH₄OH in methanol)/methylene chloride as theeluting solvent gave the title compound as brown solids (22% yield).M.p. 124-128° C., LCMS: m/z=326 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.00(m, 1H), 2.08 (s, 1H), 2.62 (t, J=5.0 Hz, 4H), 3.49 (m, 2H), 3.58 (m,2H), 3.63 (t, J=5.0 Hz, 4H), 4.85 (t, J=4.0 Hz, 1H), 6.68 (s, 1H), 6.71(s, 1H), 7.59 (dd, J=2.6, 8.8 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 8.01 (d,J=2.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H).

Example 270[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methyl-piperazin-1-yl)methanone

6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (300 mg) was reactedwith(4-methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methanone(450 mg) as in General Procedure 13. Basic alumina chromatography usinga gradient of 0-10% methanol/ethyl acetate as the eluting solvent gavethe title compound as a white foam (49% yield). LCMS: m/z=353 (M+H⁺),¹H-NMR (DMSO-d₆, 400 MHz) δ 1.78 (m, 1H), 2.19 (s, 3H), 2.32 (bs, 4H),3.27 (m, 1H), 3.36 (m, 1H), 3.50 (bs, 4H), 4.65 (m, 1H), 5.27 (d, J=4.8Hz, 1H), 6.81 (s, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H),7.71 (d, J=2.2 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H).

Example 2716-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine

6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (225 mg) was reactedwith 3-chlorophenol (0.30 mL) as in General Procedure 12. Basic aluminachromatography using a gradient of 0-1% methanol/methylene chloride asthe eluting solvent gave the title compound as a white film (60% yield).LCMS: m/z=339 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.00 (m, 1H), 2.21 (m,1H), 3.40 (m, 1H), 3.51 (m, 1H), 5.04 (s, 1H), 5.27 (t, J=3.9 Hz, 1H),6.87 (d, J=8.3 Hz, 1H), 7.00 (m, 2H), 7.24 (m, 1H), 7.48 (d, J=2.1 Hz,1H), 8.06 (d, J=2.1 Hz, 1H).

Example 272{4-[5-(2,5-Dichlorophenoxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]phenyl}-(4-methyl-piperazin-1-yl)methanone

[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone(26 mg) was reacted with 2,5-chlorophenol (22 mg) as in GeneralProcedure 12. Silica gel chromatography using a gradient of 0-10%methanol/CH₂Cl₂ as the eluting solvent gave the title compound as anoff-white film (33% yield). LCMS: m/z=497 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.12 (m, 1H), 2.37 (m, 1H), 2.71 (s, 3H), 2.98 (bs, 4H), 3.59 (m,1H), 3.79 (m, 1H), 3.97 (bs, 4H), 4.95 (m, 1H), 5.36 (s, 1H), 7.03 (d,J=8.3 Hz, 1H), 7.11 (s, 1H) 7.34 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.1 Hz,2H), 7.48 (d, J=8.1 Hz, 2H), 7.67 (s, 1H), 8.14 (s, 1H).

Example 2734-(2-Chloro-3,6-difluorophenoxy)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine

6-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol(85 mg) was reacted with 2-chloro-3,6-difluorophenol (50 mg) as inGeneral Procedure 12. Silica gel chromatography using a gradient of0-10% methanol/CH₂Cl₂ as the eluting solvent gave the title compound asa yellow foam (54% yield). LCMS: m/z=472 (M+H⁺), ¹H-NMR (DMSO-d₆, 400MHz) δ 1.89 (m, 1H), 2.21 (s, 3H), 2.24 (m, 1H), 2.39 (t, J=4.8 Hz, 4H),3.40 (m, 1H), 3.47 (t, J=4.8 Hz, 4H), 3.63 (m, 1H), 6.82 (d, J=8.8 Hz,1H), 7.03 (d, J=2.3 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H) 7.25 (m, 1H), 7.39(m, 1H), 7.52 (dd, J=2.5, 8.8 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 8.19 (d,J=2.5 Hz, 1H).

Example 274{4-[5-(3-Chlorophenoxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]-phenyl}-(4-methylpiperazin-1-yl)methanone

[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone(20 mg) was reacted with 3-chlorophenol (21.8 mg) as in GeneralProcedure 12. Silica gel chromatography using a gradient of 0-15%methanol/CH₂Cl₂ as the eluting solvent gave the title compound as ayellow foam (50% yield). LCMS: m/z=463.12(M+H⁺), ¹H-NMR (CDCl₃, 400 MHz)δ 2.00-2.12 (m, 1H), 2.27-2.33 (m, 1H), 2.33 (s, 3H), 2.34-2.6 (m, 4H),3.4-3.7 (m, 4H), 3.7-3.9 (m, 2H), 5.18 (bs, 1H), 5.38 (t, J=3.6 Hz, 1H),6.91 (dd, J=1.6 and 8.3 Hz, 1H), 6.99-7.04 (m, 2H), 7.23-7.27 (m, 1H),7.43-7.50 (m, 4H), 7.61 (d, J=2.0 Hz), 8.30 (d, J=2.2 Hz).

Example 275{4-[5-(3,5-Dichlorophenoxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]phenyl}-(4-methylpiperazin-1-yl)methanone

[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone(20 mg) was reacted with 3,5-dichlorophenol (27.7 mg) as in GeneralProcedure 12. Silica gel chromatography using a gradient of 0-15%methanol/CH₂Cl₂ as the eluting solvent gave the title compound as ayellow foam (82% yield). LCMS: m/z=497.12 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.02-2.13 (m, 1H), 2.24-2.35 (m, 1H), 2.33 (s, 3H), 2.35-2.60 (m,4H), 3.40-3.66 (m, 4H), 3.70-3.92 (m, 2H), 5.30 (bs, 1H), 5.37 (t, J=3.3Hz, 1H), 6.93 (d, J=1.6 Hz, 2H), 7.02 (dd, J=1.6 and 1.6 Hz, 1H),7.44-7.51 (m, 4H), 7.60 (d, J=2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H).

Example 276(4-Methylpiperazin-1-yl)-{4-[5-(pyridine-3-yloxy)-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]phenyl}methanone

[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone(20 mg) was reacted with 3-hydroxypyridine (16.2 mg) as in GeneralProcedure 12. Silica gel chromatography using a gradient of 0-15%methanol/CH₂Cl₂ as the eluting solvent gave the title compound as ayellow foam (20% yield). LCMS: m/z=430.17 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 2.02-2.12 (m, 1H), 2.30-2.34 (m, 1H), 2.33 (s, 3H), 2.34-2.56 (m,4H), 3.40-3.70 (m, 4H), 3.70-3.90 (m, 2H), 5.24 (bs, 1H), 5.44 (t, J=3.5Hz, 1H), 7.26-7.29 (m, 1H), 7.31-7.37 (m, 1H), 7.41-7.50 (m, 4H), 7.58(d, J=2.0 Hz, 1H), 8.28-8.33 (m, 2H), 8.43 (d, J=2.5 Hz, 1H).

Example 2771-(4-Fluoro-2-{6-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-yloxy}phenyl)ethanone

[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-4-methylpiperazin-1-yl)methanone(30 mg) was reacted with 1-(4-fluoro-2 -hydroxyphenyl)ethanone (39.4 mg)as in General Procedure 12. Silica gel chromatography using a gradientof 0-15% methanol/CH₂Cl₂ as the eluting solvent gave the title compoundas a yellow foam (53% yield). LCMS: m/z=489.14 (M+H⁺), ¹H-NMR (CDCl₃,400 MHz) δ 2.11-2.25 (m, 2H), 2.32 (s, 3H), 2.32-2.58 (m, 4H), 2.45 (s,3H), 3.40-3.68 (m, 4H), 3.70-3.90 (m, 2H), 5.31 (bs, 1H), 5.51 (t, J=3.3Hz, 1H), 6.75-6.82 (m, 1H), 6.89 (dd, J=2.1 and 10.7 Hz, 1H), 7.41-7.51(m, 4H), 7.57-7.61 (m, 1H), 7.80 (dd, J=7.1 and 8.6 Hz, 1H, 8.33 (bs,1H).

Example 2784-(3-Chlorophenoxy)-6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine

6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20mg) was reacted with1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine(25 mg) as in General Procedure 13. Silica gel chromatography using agradient of 0-100% ethyl acetate/hexane as the eluting solvent gave thetitle compound as a white foam (36% yield). LCMS: m/z=436.06 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 2.0-2.11 (m, 1H), 2.24-2.40 (m, 1H), 2.35 (s,3H), 2.54 (t, J=4.9 Hz, 4H), 3.4-3.51 (m, 1H), 3.57-3.68 (m, 5H), 5.27(bs, 1H), 5.38 (t, J=3.4 Hz, 1H), 6.64 (s, 1H), 6.73 (dd, J=1.0 and 5.2Hz, 1H), 6.90 (dd, J=2.2 and 8.3 Hz, 1H), 6.95-7.03 (m, 1H), 7.04-7.08(m, 1H), 7.22-7.28 (m, 1H), 7.57 (d, J=1.9 Hz, 1H), 8.17 (d, J=5.2 Hz,1H), 8.31 (d, J=2.2 Hz).

Example 2794-(3-Chlorophenoxy)-6-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine

6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20mg) was reacted with4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]morpholine(23.9 mg) as in General Procedure 13. Silica gel chromatography using agradient of 0-100% ethyl acetate/hexane as the eluting solvent gave thetitle compound as a yellow foam (49% yield). LCMS: m/z=422.18 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 2.00-2.11 (m, 1H), 2.22-2.26 (m, 1H), 3.19 (t,J=4.8 Hz, 4H), 3.40-3.45 (m, 1H), 3.58-3.64 (m, 1H), 3.88 (t, J=4.8 Hz,4H), 5.14 (bs, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.82-6.92 (m, 2H), 6.92 (s,1H), 6.95-7.02 (m, 2H), 7.03-7.08 (m, 1H), 7.20-7.33 (m, 2H), 7.55 (d,J=1.9 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H).

Example 2804-(3-Chlorophenoxy)-6-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine

6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20mg) was reacted with 4-morpholinophenylboronic acid (20.7 mg) as inGeneral Procedure 13. Silica gel chromatography using a gradient of0-100% ethyl acetate/hexane as the eluting solvent gave the titlecompound as a yellow solid (73% yield). M.p. 124-126° C., LCMS:m/z=422.28 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.0-2.11 (m, 1H), 2.22-2.5(m, 1H), 3.17 (t, J=4.7 Hz, 4H), 3.38-3.48 (m, 1H), 3.54-3.67 (m, 1H),3.87 (t, J=4.7 Hz, 4H), 5.10 (s, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.88-7.02(m, 4H), 7.03-7.07 (m, 1H), 7.21-7.26 (m, 1H), 7.37 (d, J=8.6 Hz, 2H),7.56 (d, J=1.9 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H).

Example 2814-(3-Chlorophenoxy)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine

6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20mg) was reacted with1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine(25.0 mg) as in General Procedure 13. Silica gel chromatography using agradient of 0-20% methanol/CH₂Cl₂ as the eluting solvent gave the titlecompound as an orange foam (55% yield). LCMS: m/z=436.12 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 2.0-2.11 (m, 1H), 2.21-2.32 (m, 1H), 2.36 (s, 3H),2.54 (t, J=5.0 Hz, 4H), 3.39-3.49 (m, 1H), 3.53-3.68 (m, 1H), 3.59 (t,J=5.0 Hz, 4H), 5.10 (s, 1H), 5.37 (t, J=3.5 Hz, 1H), 6.68 (d, J=8.8 Hz,1H), 6.90 (dd, J=2.3 and 8.3 Hz, 1H), 6.98-7.07 (m, 2H), 7.20-7.27 (m,1H), 7.50 (d, J=2.1 Hz, 1H), 7.56 (dd, J=2.5 and 8.8 Hz, 1H), 8.20 (d,J=2.2 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H).

Example 2827-Bromo-4-[1-iodomethylidene]-1,2,3,4-tetrahydro-[1,8]naphthyridine

To a suspension of 7-bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one (1.5g) in anhydrous tetrahydrofuran (195 mL) was added a solution of CrCl₂(6.79 g, 8.35 eq) and CHI₃ (5.55 g, 2.13 eq) in anhydroustetrahydrofuran (66 mL). The reaction was stirred at room temperaturefor 16 hours, diluted with methylene chloride (300 mL), and then washedwith saturated NaHCO₃ (300 mL). The aqueous phase was extracted twicewith methylene chloride (100 mL) and the combined organic layers werewashed with brine and then dried over Na₂SO₄. The solution was filteredand concentrated under reduced pressure. Silica gel chromatography usinga gradient of 0-30% ethyl acetate/hexane as the eluting solvent gave thetitle compound as a yellow solid (27% yield). Alkene geometry wasdetermined by nOe. LCMS: m/z=352 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 2.69(t, J=6.0 Hz, 2H), 3.43-3.51 (m, 2H), 5.25 (bs, 1H), 6.23 (s, 1H), 6.74(d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H).

Example 2837-Bromo-4-[1-(2,5-difluorophenyl)methylidene]-1,2,3,4-tetrahydro-[1,8]naphthyridine

Na₂CO₃ (2N, 3.46 mL, 10.0 eq) was added to a mixture of7-bromo-4-[1-iodomethylidene]-1,2,3,4-tetrahydro-[1,8]naphthyridine (607mg), 2,5-difluorophenylboronic acid (328 mg, 1.2 eq), and Pd(PPh₃)₄ (150mg, 0.075 eq) in toluene/ethanol (4:1 v/v). The reaction was heated at85° C. for five (5) hours, Celite was added, and the mixture was thenconcentrated under reduced pressure. The dry powder was then dry loadedonto a silica gel column and a gradient of 0-20% ethyl acetate/hexane asthe eluting solvent gave the title compound as a yellow solid (70%yield). M.p. 178-179° C., LCMS: m/z=337 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz)δ 2.62 (t, J=5.8 Hz, 2H), 3.55-3.62 (m, 2H), 5.25 (bs, 1H), 6.26 (s,1H), 6.45 (d, J=7.9 Hz, 1H), 6.85-6.95 (m, 1H), 6.96-7.12 (m, 3H).

Example 284 4-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine

7-Bromo-4-[1-(2,5-difluorophenyl)methylidene]-1,2,3,4-tetrahydro-[1,8]naphthyridine(200 mg) was dissolved in methanol (20 mL) and Pd/C (20 mg) was added.The reaction was hydrogenated at atmospheric pressure for 1.5 hours,filtered through Celite, and then concentrated under reduced pressure togive the title compound as a clear colorless oil (near quantitativeyield). LCMS: m/z=261.11 (M+H⁺), ¹H-NMR (MeOH-d₄, 400 MHz) δ 1.68-1.86(m, 2H), 2.80 (dd, J=9.0 and 13.3, 1H), 2.96 (dd, J=10.0 and 13.3 Hz,1H), 3.02-3.12 (m, 1H), 3.34-3.41 (m, 1H), 3.46-3.55 (m, 1H), 6.44 (dd,J=5.2 and 7.2 Hz, 1H), 6.93-7.03 (m, 2H), 7.03-7.11 (m, 2H), 7.72 (dd,J=1.0 and 5.0 Hz, 1H).

Example 2856-Bromo-4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine

To a solution of4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (23 mg) inCH₂Cl₂/acetic acid (5.5 mL, 10:1, v/v) was added N-bromosuccinimide(18.8 mg, 1.2 eq). The reaction was stirred at room temperature for one(1) hour, concentrated under reduced pressure, and purified by silicagel chromatography using a gradient of 0-60% ethyl acetate/hexane as theeluting solvent to give the title compound as a clear, colorless oil(30% yield). LCMS: m/z=339 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.66-1.75(m, 1H), 1.75-1.86 (m, 1H), 2.73 (dd, J=9.6 and 13.4 Hz, 1H), 2.95 (dd,J=6.0 and 13.4 Hz, 1H), 2.99-3.08 (m, 1H), 3.34-3.43 (m, 1H), 3.45-3.55(m, 1H), 5.22 (bs, 1H), 6.80-6.86 (m, 1H), 6.88-6.96 (m, 1H), 6.98-7.05(m, 1H), 7.16 (d, J=1.9 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H).

Example 2864-(2,5-Difluorobenzyl)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine

Na₂CO₃ (2N, 53 μL) (4.0 eq) was added to a mixture of6-bromo-4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine(9.0 mg) (1 eq),1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine(11.3 mg) (1.4 eq), and Pd(PPh₃)₄ (3.0 mg, 0.1 eq) in toluene/ethanol(4:1, v/v, 2 mL). The reaction was heated at 90° C. for six (6) hours.The reaction mixture was then concentrated under reduced pressure andthe residue was taken up in CH₂Cl₂ (15 mL) and washed with water (15mL). The organic phase was dried over Na₂SO₄, filtered, concentratedunder reduced pressure, and purified by silica gel chromatography usinga gradient of 0-20% methanol/CH₂Cl₂ as the eluting solvent to give thetitle compound as a yellow foam (26% yield). LCMS: m/z=436 (M+H⁺),¹H-NMR (CDCl₃, 400 MHz) δ 1.7-2.0 (m, 2H), 2.37 (s, 3H), 2.55-2.60 (m,4H), 2.81 (dd, J=9.1 and 13.3 Hz, 1H), 2.98 (dd, J=6.4 and 13.3H, 1H),3.08-3.18 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.70 (m, 5H), 5.18 (bs, 1H),6.68 (d, J=8.8 Hz, 1H), 6.81-6.87 (m, 1H), 6.89-6.96 (m, 1H), 6.98-7.06(m, 1H), 7.16 (d, J=1 Hz, 1H), 7.50 (dd, J=2.5 and 8.8 Hz, 1H), 8.05 (d,J=1 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H).

Example 287(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-morpholin-4-yl-piperidin-1-yl)methanone

4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoicacid (70 mg) was reacted with 4-piperidin-4-yl-morpholine as in GeneralProcedure 8 to give the title compound as a light yellow foam (43%yield). M.p. (foam), LCMS: m/z=600.14 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ1.42-1.58 (m, 2H), 1.72-1.94 (m, 2H), 2.35-2.45 (m, 1H), 2.52-2.58 (m,4H), 2.86-3.03 (m, 2H), 3.47-3.53 (m, 2H), 3.63-3.74 (m, 6H), 3.88-3.96(m, 1H), 4.58 (s, 2H), 5.12 (s, 1H), 6.59 (d, J=8.3 Hz, 1H), 7.32-7.49(m, 5H), 7.64 (d, J=8.3 Hz, 1H), 7.74 (d, J=1.76 Hz, 1H).

Example 288(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thiazol-2-yl-piperazin-1-yl)methanone

4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoicacid (70 mg) was reacted with 1-thiazol-2-yl-piperazine as in GeneralProcedure 8 to give the title compound as a yellow solid (61% yield).M.p. 243-244, LCMS: m/z=598.92 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.49-3.92 (m, 12H), 4.63 (s, 2H), 5.06 (bs, 1H), 6.57-6.64 (m, 2H), 7.21(d, J=3.52 Hz, 1H), 7.35-7.43 (m, 5H), 7.51 (s, 1H), 7.65 (d, J=8.4 Hz,1H), 7.76 (s, 1H).

Example 2893,6-Difluoro-2-[7-(6-morpholin-4-yl-pyridin-3-yl)-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-ylmethyl]benzonitrile

1-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(300 mg) was dissolved in anhydrous DMF. CuCN (5.0 eq) was added and theresulting mixture was heated to 150° C. in a microwave for 30 minutes.The reaction mixture was concentrated, taken up in CH₂Cl₂, washed three(3) times with an aqueous solution of NH₄OH (10%), and the organic phasewas dried, filtered, and concentrated. The residue was purified viasilica gel chromatography (0-100% ethyl acetate in hexanes followed by5% methanol in ethyl acetate) to give the title compound (37% yield).M.p 188-190° C., LCMS: m/z=449.05 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ3.24-3.31 (m, 2H), 3.48-3.56 (m, 6H), 3.80-3.88 (m, 4H), 4.51 (s, 2H),4.86 (bs, 1H), 6.65-6.73 (m, 1H), 6.98-7.06 (m, 2H), 7.09-7.19 (m, 2H),7.59-7.64 (m, 2H), 8.36 (s, 1H).

Example 2907-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (659 mg) was reactedwith 2-(chloromethyl)-5-(trifluoromethyl)furan as in General Procedure 1to give the title compound as a beige solid (87% yield). M.p. 189-191°C., LCMS: m/z=424.20 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 4.21 (s, 2H),4.95 (bs, 1H), 5.05 (s, 2H), 6.39 (s, 1H), 6.75 (s, 1H), 7.50 (s, 1H),7.96 (s, 1H).

Example 2917-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(860 mg) was reduced as in General Procedure 3 to give the titlecompound as a white solid (18% yield). M.p. 153-154° C., LCMS:m/z=409.89 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 3.33-3.40 (m, 2H),3.47-3.59 (m, 2H), 4.38 (s, 2H), 5.10 (bs, 1H), 6.28 (s, 1H), 6.73 (s,1H), 6.90 (s, 1H), 7.61 (s, 1H).

Example 2927-(6-Morpholin-4-yl-pyridin-3-yl)-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(60 mg) was reacted with4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholineas in General Procedure 4A to give the title compound as an orange foam(30% yield). M.p. (foam), LCMS: m/z=446.13 (M+H⁺), ¹H-NMR (CDCl₃, 400MHz) δ 3.42-3.47 (m, 2H), 3.48-3.54 (m, 4H), 3.58-3.67 (m, 2H),3.80-3.89 (m, 4H), 4.47 (s, 1H), 5.02 (bs, 1H), 6.30 (s, 1H), 6.67 (d,J=5.2 Hz, 1H), 6.72 (s, 1H), 6.85 (s, 1H), 7.55-7.62 (m, 2H), 8.31 (s,1H).

Example 2937-[2-(4-Methylpiperazin-1-yl)pyridin-4-yl]-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(60 mg) was reacted with1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazineas in General Procedure 4A to give the title compound as a beige foam(30% yield). M.p. (foam), ¹H-NMR (CDCl₃, 400 MHz) δ 2.31-3.36 (m, 4H),2.38-2.53 (m, 4H), 3.42-3.48 (m, 2H), 3.48-3.58 (m, 1H), 3.61-3.66 (m,2H), 3.74-3.84 (m, 2H), 5.02 (bs, 1H), 6.31 (s, 1H), 6.74 (s, 1H), 6.93(s, 1H), 7.41-7.50 (m, 3H), 7.73 (s, 1H).

Example 2947-Iodo-1-[2-(trifluoromethoxy)benzyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (942 mg) was reactedwith 2-(trifluoromethoxy)benzyl bromide as in General Procedure 1 togive the title compound as a light yellow solid (61% yield). m.p.=235°C., LCMS: m/z=449.92 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 4.29 (2H, s),4.89 (1H, s), 5.16 (2H, s), 7.09 (2H, m), 7.24 (1H, m), 7.34 (2H, m),7.92 (1H, s).

Example 2951-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid [4-(dimethylamino)butyl]amide

4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoicacid (84 mg) was reacted with 4-(dimethylamino)butylamine as in GeneralProcedure 8 to give the title compound as a yellow solid (45% yield).m.p.=182° C., LCMS: m/z=545.86 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.60(2H, m), 1.69 (2H, m), 2.20 (6H, s), 2.31 (2H, m), 3.43 (2H, m), 3.49(2H, m), 3.69 (2H, m), 4.62 (2H, s), 5.27 (1H, bs), 6.61 (1H, s), 7.35(1H, d, J=8.3 Hz), 7.39 (2H, d, J=7.8 Hz), 7.51 (1H, s), 7.63 (1H, d,J=8.3 Hz), 7.70 (1H, m), 7.75 (3H, m).

Example 2967-Iodo-1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

7-Iodo-1-[2-(trifluoromethoxy)benzyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(940 mg) was reduced as in General Procedure 3 to give the titlecompound as a brown sticky solid. LCMS: m/z=435.82 (M+H⁺), ¹H-NMR(CDCl₃, 400 MHz) δ 3.38 (2H, m), 3.55 (2H, m), 4.44 (2H, s), 4.95 (1H,s), 6.71 (1H, s), 7.30 (4H, m), 7.59 (1H, s).

Example 2974-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester

7-Iodo-1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(699 mg) was reacted with (4-ethoxycarbonylphenyl)boronic acid as inGeneral Procedure 4B to give the title compound as a yellow solid.m.p.=153° C., LCMS: m/z=458.00 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.38(3H, t, J=7.1 Hz), 3.47 (2H, m), 3.64 (2H, m), 4.36 (2H, quartet, J=7.1Hz), 4.56 (2H, s), 5.22 (1H, bs), 6.73 (1H, s), 7.25 (1H, m), 7.31 (2H,m), 7.37 (1H, d, J=7.3 Hz), 7.42 (2H, d, J=7.8. Hz), 7.75 (1H, s), 8.00(2H, d, J=8.1 Hz).

Example 2984-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid

4-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester (356 mg) was saponified as in General Procedure 7 togive the title compound as an orange solid (76% yield). m.p.=250° C.,LCMS: m/z=430.14 (M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.55 (2H, s), 4.70(2H, s), 7.03 (1H, s), 7.43 (4H, m), 7.61 (2H, d, J=8.1 Hz), 7.72 (1H,s), 7.93 (2H, d, J=8.1 Hz).

Example 2991-(2-Chloropyridin-3-ylmethyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.189 g) was reactedwith 3-(bromomethyl)-2-chloropyridine as in General Procedure 1 to givethe title compound as an orange solid (58% yield). m.p.=249° C., LCMS:m/z=401.18 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 4.29 (2H, s), 5.16 (2H, s),7.04 (1H, s), 7.26 (1H, m), 7.36 (1H, d, J=7.6 Hz), 7.91 (1H, s), 8.34(1H, d, J=4.3 Hz).

Example 3001-(2-Chloropyridin-3-ylmethyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

1-(2-Chloropyridin-3-ylmethyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one(1.005 g) was reduced as in General Procedure 3 to give the titlecompound as a brown sticky solid. LCMS: m/z=387.16 (M+H⁺).

Example 3014-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester

1-(2-Chloropyridin-3-ylmethyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(389 mg) was reacted with (4-ethoxycarbonylphenyl) boronic acid as inGeneral Procedure 4B to give the title compound as a yellow solid. LCMS:m/z=409.34 (M+H⁺).

Example 3024-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid

4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester (51 mg) was saponified as in General Procedure 7 togive the title compound as a yellow solid (82% yield). LCMS: m/z=381.29(M+H⁺), ¹H-NMR (DMSO-d₆, 400 MHz) δ 4.64 (2H, s), 6.87 (1H, s), 7.40(1H, m), 7.60 (2H, d, J=8.3 Hz), 7.74 (2H, m), 7.90 (2H, d, J=8.3 Hz),8.34 (1H, m).

Example 303{4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)methanone

4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid (38 mg) was reacted with 4-(1-pyrrolidinyl)piperidine as in GeneralProcedure 8 to give the title compound as a yellow solid (20% yield).LCMS: m/z=516.89 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.50 (1H, m), 1.80(5H, m), 1.97 (2H, m), 2.27 (1H, m), 2.58 (4H, m), 3.01 (2H, m), 3.50(2H, m), 3.67 (2H, m), 3.79 (1H, m), 4.54 (2H, s), 4.95 (1H, bs), 6.58(1H, d, J=1.5 Hz), 7.23 (1H, m), 7.36 (4H, m), 7.62 (1H, dd, J=7.6, 1.8Hz), 7.73 (1H, d, J=1.8 Hz), 8.34 (1H, dd, J=4.8, 1.8 Hz).

Example 304N-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)acetamide

1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine(90 mg) was reacted with 4-acetamidophenylboronic acid as in GeneralProcedure 4B to give the title compound as a light gray solid (42%yield). m.p.=244° C., LCMS: m/z=461.24 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ2.13 (3H, s), 3.49 (2H, m), 3.65 (2H, m), 3.82 (2H, s), 4.61 (2H, s),6.58 (1H, s), 7.28 (2H, d, J=8.1 Hz), 7.36 (1H, d, J=7.3 Hz), 7.51 (3H,m), 7.60 (1H, s), 7.65 (1H, d, J=8.6 Hz).

Example 305(4-Pyrrolidin-1-yl-piperidin-1-yl)-(4-{1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid (98 mg) was reacted with 4-(1-pyrrolidinyl)piperidine as in GeneralProcedure 8 to give the title compound as a yellow solid (65% yield).LCMS: m/z=565.98 (M+H⁺), ¹H-NMR (CDCl₃, 400 MHz) δ 1.53 (2H, bs), 2.88(7H, m), 2.27 (1H, m), 2.57 (4H, s), 2.98 (2H, m), 3.46 (2H, m), 3.63(2H, m), 3.81 (1H, bs), 4.55 (2H, s), 5.21 (1H, s), 6.71 (1H, s), 7.33(8H, m), 7.71 (1H, s).

Example 306(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperazin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-phenylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=591.97 (M+H⁺); retention time=0.97minutes.

Example 307(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(2-pyrimidinyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=593.97 (M+H⁺);retention time=0.84 minutes.

Example 308[4-(4-Chlorophenyl)-piperazin-1-yl]-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=625.95 (M+H⁺);retention time=1.05 minutes.

Example 309[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=640.96(M+H⁺); retention time=0.95 minutes.

Example 3101-[1-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-1,3-dihydrobenzoimidazol-2-one

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1,3-dihydro-1-(4-piperidinyl)benzoimidazol-2-oneas in General Procedure 10 to give the title compound. LCMS: m/z=647.02(M+H⁺); retention time=0.83 minutes.

Example 311(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(2-methoxyphenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=621.97 (M+H⁺);retention time=0.95 minutes.

Example 312(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-[3-(trifluoromethyl)phenyl]piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=659.98(M+H⁺); retention time=1.07 minutes.

Example 313(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-phenylpiperidine as in General Procedure 10 togive the title compound. LCMS: m/z=590.98 (M+H⁺); retention time=1.03minutes.

Example 314(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(1H-indol-3-yl)piperidin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(1H-indol-3-yl)piperidine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=630.02 (M+H⁺);retention time=0.98 minutes.

Example 315(4-Benzhydrylpiperazin-1-yl)-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-benzhydrylpiperazine as in General Procedure 10to give the title compound. LCMS: m/z=680.97 (M+H⁺); retention time=1.03minutes.

Example 316(4-Benzylpiperidin-1-yl)-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-benzylpiperidine as in General Procedure 10 togive the title compound. LCMS: m/z=605.01 (M+H⁺); retention time=1.09minutes.

Example 317(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(3,4-dichlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=661.88 (M+H⁺);retention time=1.11 minutes.

Example 3188-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as inGeneral Procedure 10 to give the title compound. LCMS: m/z=661.00(M+H⁺); retention time=0.87 minutes.

Example 319(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-[2-(trifluoromethyl)phenyl]piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=659.99(M+H⁺); retention time=1.1 minutes.

Example 320(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-ylpiperazin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-thieno[3,2-d]pyrimidinyl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=649.98(M+H⁺); retention time=0.65 minutes.

Example 321[4-(4-Chlorobenzyl)piperazin-1-yl]-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-chlorobenzyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=639.99 (M+H⁺);retention time=0.7 minutes.

Example 322(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-methoxybenzyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=636.01 (M+H⁺);retention time=0.62 minutes.

Example 323(4-Benzoylpiperazin-1-yl)-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-benzoylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=619.98 (M+H⁺); retention time=0.82minutes.

Example 324(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-furo[3,2-c]pyridin-4-ylpiperazin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-furo[3,2-c]pyridinyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=633.99 (M+H⁺);retention time=0.64 minutes.

Example 325(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=649.95(M+H⁺); retention time=1.00 minutes.

Example 3264-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoylamino)piperidine-1-carboxylicacid ethyl ester

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-aminopiperidine-1-carboxylic acid ethyl ester asin General Procedure 10 to give the title compound. LCMS: m/z=601.99(M+H⁺); retention time=0.86 minutes.

Example 327N-(1-Benzylpiperidin-4-yl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-amino-1-benzylpiperidine as in General Procedure10 to give the title compound. LCMS: m/z=619.96 (M+H⁺); retentiontime=0.62 minutes.

Example 3283-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2,2-diphenylethylamine as in General Procedure 10to give the title compound. LCMS: m/z=626.96 (M+H⁺); retention time=1.06minutes.

Example 3293-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(1-methylpiperidin-4-yl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-amino-1-methylpiperidine as in General Procedure10 to give the title compound. LCMS: m/z=543.99 (M+H⁺); retentiontime=0.53 minutes.

Example 330(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-piperazinyl-2-(2-pyridinyl)ethane as in GeneralProcedure 10 to give the title compound. LCMS: m/z=620.99 (M+H⁺);retention time=0.55 minutes.

Example 3313-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(trifluoromethoxy)benzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=620.94 (M+H⁺);retention time=1.04 minutes.

Example 332N-[3,5-Bis(trifluoromethyl)benzyl]-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=672.88 (M+H⁺);retention time=1.11 minutes.

Example 333N-Benzhydryl-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with benzhydrylamine as in General Procedure 10 to givethe title compound. LCMS: m/z=612.98 (M+H⁺); retention time=1.06minutes.

Example 3343-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-4-ylmethylbenzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10to give the title compound. LCMS: m/z=537.96 (M+H⁺); retention time=0.56minutes.

Example 3353-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-3-ylmethylbenzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10to give the title compound. LCMS: m/z=538 (M+H⁺); retention time=0.59minutes.

Example 3362-[4-(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]-N-isopropylacetamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-piperazinyl-N-isopropylacetamide as in GeneralProcedure 10 to give the title compound. LCMS: m/z=615.01 (M+H⁺);retention time=0.61 minutes.

Example 337(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-methyl-4-(1-piperazinyl)quinoline as in GeneralProcedure 10 to give the title compound. LCMS: m/z=656.99 (M+H⁺);retention time=0.61 minutes.

Example 3383-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=629.94 (M+H⁺);retention time=0.77 minutes.

Example 339(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(1-piperazinyl)pyrazine as in General Procedure10 to give the title compound. LCMS: m/z=593.97 (M+H⁺); retentiontime=0.78 minutes.

Example 3403-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in GeneralProcedure 10 to give the title compound. LCMS: m/z=619.9 (M+H⁺);retention time=0.99 minutes.

Example 341(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)morpholin-4-ylmethanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with morpholine as in General Procedure 10 to give thetitle compound. LCMS: m/z=516.96 (M+H⁺); retention time=0.76 minutes.

Example 3423-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-naphthalen-1-ylmethylbenzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(aminomethyl)naphthalene as in General Procedure10 to give the title compound. LCMS: m/z=586.96 (M+H⁺); retentiontime=1.02 minutes.

Example 3433-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-1-ylbenzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-aminoindan as in General Procedure 10 to givethe title compound. LCMS: m/z=562.95 (M+H⁺); retention time=0.99minutes.

Example 344(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3-methoxyphenyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(3-methoxyphenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=622.01 (M+H⁺);retention time=0.97 minutes.

Example 345(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-methoxyphenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=621.98 (M+H⁺);retention time=0.92 minutes.

Example 3463-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-cyclohexylbenzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with cyclohexylamine as in General Procedure 10 to givethe title compound. LCMS: m/z=529.01 (M+H⁺); retention time=0.96minutes.

Example 3473-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methanesulfonylbenzyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-methanesulfonylbenzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=614.91 (M+H⁺);retention time=0.81 minutes.

Example 348N-(2-Chlorobenzyl)-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=570.9 (M+H⁺); retention time=0.98minutes.

Example 349N-(4-Chlorobenzyl)-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=570.9 (M+H⁺); retention time=0.99minutes.

Example 350N-(3-Chlorobenzyl)-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=570.99 (M+H⁺); retention time=0.99minutes.

Example 351(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(tetrahydrofuran-2-carbonyl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=613.98(M+H⁺); retention time=0.73 minutes.

Example 3523-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(aminomethyl)tetrahydrofuran as in GeneralProcedure 10 to give the title compound. LCMS: m/z=530.97 (M+H⁺);retention time=0.81 minutes.

Example 3533-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(3-methoxybenzyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-methoxybenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=566.99 (M+H⁺); retention time=0.93minutes.

Example 3543-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-methoxybenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=566.93 (M+H⁺); retention time=0.91minutes.

Example 3553-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-phenoxyethylamine as in General Procedure 10 togive the title compound. LCMS: m/z=566.93 (M+H⁺); retention time=0.94minutes.

Example 356N-Benzyl-3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with benzylamine as in General Procedure 10 to give thetitle compound. LCMS: m/z=536.96 (M+H⁺); retention time=0.92 minutes.

Example 357[4-(3-Chlorophenyl)piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(3-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=625.97 (M+H⁺);retention time=1.05 minutes.

Example 3583-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-2-ylbenzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-aminoindan as in General Procedure 10 to givethe title compound. LCMS: m/z=562.95 (M+H⁺); retention time=0.98minutes.

Example 359(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenethylpiperazin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-phenethylpiperazine as in General Procedure 10to give the title compound. LCMS: m/z=618.98 (M+H⁺); retention time=0.64minutes.

Example 360[4-(2-Chlorophenyl)piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(2-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=625.96 (M+H⁺);retention time=1.05 minutes.

Example 361N-(1-Benzylpyrrolidin-3-yl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-amino-1-benzylpyrrolidine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=604.99 (M+H⁺);retention time=0.63 minutes.

Example 362(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(cyclohexylmethyl)piperazin-1-yl]methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(cyclohexylmethyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=611.96 (M+H⁺);retention time=0.65 minutes.

Example 3633-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10to give the title compound. LCMS: In/z=615.9 (M+H⁺); retention time=0.77minutes.

Example 364(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-morpholin-4-ylpiperidin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(4-morpholinyl)piperidine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=598.99 (M+H⁺);retention time=0.52 minutes.

Example 365(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-((S)-2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with (S)-2-(1-pyrrolidinylmethyl)pyrrolidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=583.96(M+H⁺); retention time=0.58 minutes.

Example 366(3-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2-pyridin-3-ylpyrrolidin-1-yl)methanone

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure10 to give the title compound. LCMS: m/z=577.95 (M+H⁺); retentiontime=0.65 minutes.

Example 3673-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxybenzyl)-N-methylbenzamide

3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with N-methyl-2-methoxybenzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=580.94 (M+H⁺);retention time=0.96 minutes.

Example 368(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperazin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-phenylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=592.00 (M+H⁺); retention time=0.98minutes.

Example 369(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(2-pyrimidinyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=593.98 (M+H⁺);retention time=0.84 minutes.

Example 370[4-(4-Chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=625.96 (M+H⁺);retention time=1.06 minutes.

Example 371[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=640.96(M+H⁺); retention time=0.94 minutes.

Example 3721-[1-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-1,3-dihydrobenzoimidazol-2-one

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1,3-dihydro-1-(4-piperidinyl)benzoimidazol-2-oneas in General Procedure 10 to give the title compound. LCMS: m/z=647.03(M+H⁺); retention time=0.81 minutes.

Example 373(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(2-methoxyphenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=621.98 (M+H⁺);retention time=0.95 minutes.

Example 374(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-[3-(trifluoromethyl)phenyl]piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=659.99(M+H⁺); retention time=1.08 minutes.

Example 375(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-phenylpiperidine as in General Procedure 10 togive the title compound. LCMS: m/z=590.99 (M+H⁺); retention time=1.04minutes.

Example 376(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(1H-indol-3-yl)piperidin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(1H-indol-3-yl)piperidine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=630.92 (M+H⁺);retention time=0.99 minutes.

Example 377(4-Benzhydrylpiperazin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-benzhydrylpiperazine as in General Procedure 10to give the title compound. LCMS: m/z=680.99 (M+H⁺); retention time=1.00minutes.

Example 378(4-Benzylpiperidin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-benzylpiperidine as in General Procedure 10 togive the title compound. LCMS: m/z=605.00 (M+H⁺); retention time=1.09minutes.

Example 379(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(3,4-dichlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=659.92 (M+H⁺);retention time=1.12 minutes.

Example 3808-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as inGeneral Procedure 10 to give the title compound. LCMS: m/z=661.03(M+H⁺); retention time=0.86 minutes.

Example 381(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-[2-(trifluoromethyl)phenyl]piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=659.99(M+H⁺); retention time=1.10 minutes.

Example 382(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-thieno[3,2-d]pyrimidinyl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=648.99(M+H⁺); retention time=0.64 minutes.

Example 383[4-(4-Chlorobenzyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-chlorobenzyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=639.99 (M+H⁺);retention time=0.69 minutes.

Example 384(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-methoxybenzyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=636.02 (M+H⁺);retention time=0.61 minutes.

Example 385(4-Benzoylpiperazin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-benzoylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=619.98 (M+H⁺); retention time=0.82minutes.

Example 386(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-furo[3,2-c]pyridin-4-ylpiperazin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-furo[3,2-c]pyridinyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=633.03 (M+H⁺);retention time=0.63 minutes.

Example 387(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=649.96(M+H⁺); retention time=1.00 minutes.

Example 3884-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-pyridin-2-yl-ethyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(2-pyridinyl)ethylamine as in General Procedure10 to give the title compound. LCMS: m/z=551.01 (M+H⁺); retentiontime=0.56 minutes.

Example 3894-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoylamino)piperidine-1-carboxylicacid ethyl ester

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-aminopiperidine-1-carboxylic acid ethyl ester asin General Procedure 10 to give the title compound. LCMS: m/z=601.99(M+H⁺); retention time=0.85 minutes.

Example 390N-(1-Benzylpiperidin-4-yl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-amino-1-benzylpiperidine as in General Procedure10 to give the title compound. LCMS: m/z=619.99 (M+H⁺); retentiontime=0.61 minutes.

Example 3914-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2,2-diphenylethylamine as in General Procedure 10to give the title compound. LCMS: m/z=626.99 (M+H⁺); retention time=1.06minutes.

Example 3921-[4-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]ethanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-acetylpiperazine as in General Procedure 10 togive the title compound. LCMS: m/z=557.97 (M+H⁺); retention time=0.68minutes.

Example 3934-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(1-methylpiperidin-4-yl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-amino-1-methylpiperidine as in General Procedure10 to give the title compound. LCMS: m/z=543.96 (M+H⁺); retentiontime=0.51 minutes.

Example 394(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-piperazinyl-2-(2-pyridinyl)ethane as in GeneralProcedure 10 to give the title compound. LCMS: m/z=620.98 (M+H⁺);retention time=0.53 minutes.

Example 3954-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(trifluoromethoxy)benzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=620.95 (M+H⁺);retention time=1.03 minutes.

Example 3964-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethyl)benzyl]benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(trifluoromethyl)benzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=604.92 (M+H⁺);retention time=1.01 minutes.

Example 397N-[3,5-Bis(trifluoromethyl)benzyl]-4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=672.90 (M+H⁺);retention time=1.11 minutes.

Example 3984-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-thiophen-2-yl-ethyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(2-aminoethyl)thiophene as in General Procedure10 to give the title compound. LCMS: m/z=556.91 (M+H⁺); retentiontime=0.92 minutes.

Example 399N-Benzhydryl-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with benzhydrylamine as in General Procedure 10 to givethe title compound. LCMS: m/z=613.00 (M+H⁺); retention time=1.06minutes.

Example 4004-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-4-ylmethylbenzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10to give the title compound. LCMS: m/z=537.98 (M+H⁺); retention time=0.54minutes.

Example 4014-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-3-ylmethylbenzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10to give the title compound. LCMS: m/z=537.95 (M+H⁺); retention time=0.57minutes.

Example 4022-[4-(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]-N-isopropylacetamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-piperazinyl-N-isopropylacetamide as in GeneralProcedure 10 to give the title compound. LCMS: m/z=615.03 (M+H⁺);retention time=0.58 minutes.

Example 403(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-methyl-4-(1-piperazinyl)quinoline as in GeneralProcedure 10 to give the title compound. LCMS: m/z=656.96 (M+H⁺);retention time=0.62 minutes.

Example 4044-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxyethyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-methoxyethylamine as in General Procedure 10 togive the title compound. LCMS: m/z=504.97 (M+H⁺); retention time=0.74minutes.

Example 4054-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=629.94 (M+H⁺);retention time=0.75 minutes.

Example 406(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(1-piperazinyl)pyrazine as in General Procedure10 to give the title compound. LCMS: m/z=593.98 (M+H⁺); retentiontime=0.79 minutes.

Example 4074-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in GeneralProcedure 10 to give the title compound. LCMS: m/z=619.90 (M+H⁺);retention time=0.98 minutes.

Example 408(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)morpholin-4-ylmethanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with morpholine as in General Procedure 10 to give thetitle compound. LCMS: m/z=516.96 (M+H⁺); retention time=0.74 minutes.

Example 4094-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-naphthalen-1-ylmethylbenzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(aminomethyl)naphthalene as in General Procedure10 to give the title compound. LCMS: m/z=586.95 (M+H⁺); retentiontime=1.01 minutes.

Example 4104-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-1-ylbenzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-aminoindan as in General Procedure 10 to givethe title compound. LCMS: m/z=562.95 (M+H⁺); retention time=0.98minutes.

Example 411(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(4-methoxyphenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=622.01 (M+H⁺);retention time=0.92 minutes.

Example 412N-(2-Chlorobenzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=570.90 (M+H⁺); retention time=0.98minutes.

Example 413N-(4-Chlorobenzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=570.90 (M+H⁺); retention time=0.98minutes.

Example 414N-(3-Chloro-benzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-chlorobenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=570.90 (M+H⁺); retention time=0.98minutes.

Example 415(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(tetrahydrofuran-2-carbonyl)piperazine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=613.98(M+H⁺); retention time=0.72 minutes.

Example 4164-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-phenethylbenzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with phenethylamine as in General Procedure 10 to givethe title compound. LCMS: m/z=550.96 (M+H⁺); retention time=0.94minutes.

Example 4174-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(aminomethyl)tetrahydrofuran as in GeneralProcedure 10 to give the title compound. LCMS: m/z=530.96 (M+H⁺);retention time=0.78 minutes.

Example 4184-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(3-methoxybenzyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-methoxybenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=566.97 (M+H⁺); retention time=0.91minutes.

Example 4194-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-methoxybenzylamine as in General Procedure 10 togive the title compound. LCMS: m/z=566.97 (M+H⁺); retention time=0.90minutes.

Example 4204-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-phenoxyethylamine as in General Procedure 10 togive the title compound. LCMS: m/z=566.93 (M+H⁺); retention time=0.93minutes.

Example 421N-Benzyl-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with benzylamine as in General Procedure 10 to give thetitle compound. LCMS: m/z=536.96 (M+H⁺); retention time=0.91 minutes.

Example 422[4-(3-Chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(3-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=625.96 (M+H⁺);retention time=1.06 minutes.

Example 4234-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-2-ylbenzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-aminoindan as in General Procedure 10 to givethe title compound. LCMS: m/z=562.96 (M+H⁺); retention time=0.98minutes.

Example 424(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenethylpiperazin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-phenethylpiperazine as in General Procedure 10to give the title compound. LCMS: m/z=620.02 (M+H⁺); retention time=0.63minutes.

Example 425N-Biphenyl-4-ylmethyl-4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-(aminomethyl)biphenyl as in General Procedure 10to give the title compound. LCMS: m/z=613.00 (M+H⁺); retention time=1.07minutes.

Example 426[4-(2-Chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(2-chlorophenyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=625.96 (M+H⁺);retention time=1.07 minutes.

Example 427N-(1-Benzylpyrrolidin-3-yl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 3-amino-1-benzylpyrrolidine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=605.96 (M+H⁺);retention time=0.62 minutes.

Example 428(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(cyclohexylmethyl)piperazin-1-yl]methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1-(cyclohexylmethyl)piperazine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=611.96 (M+H⁺);retention time=0.64 minutes.

Example 4294-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10to give the title compound. LCMS: m/z=615.91 (M+H⁺); retention time=0.75minutes.

Example 430(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-((S)-2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with (S)-2-(1-pyrrolidinylmethyl)pyrrolidine as inGeneral Procedure 10 to give the title compound. LCMS: m/z=583.95(M+H⁺); retention time=0.58 minutes.

Example 431(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2-pyridin-3-yl-pyrrolidin-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure10 to give the title compound. LCMS: m/z=577.97 (M+H⁺); retentiontime=0.63 minutes.

Example 4324-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxybenzyl)-N-methylbenzamide

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with N-methyl-2-methoxybenzylamine as in GeneralProcedure 10 to give the title compound. LCMS: m/z=580.98 (M+H⁺);retention time=0.96 minutes.

Example 433(4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(1,3-dihydroisoindol-2-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with 1,3-dihydroisoindole as in General Procedure 10 togive the title compound. LCMS: m/z=548.94 (M+H⁺); retention time=0.94minutes.

Example 434{4-[1-(5-Chloro-2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-phenyl}-(spiro[isobenzofuran-1(3H),4′-piperidine]-1-yl)methanone

4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid was reacted with spiro(isobenzofuran-1(3H), 4′-piperidine) as inGeneral Procedure 10 to give the title compound. LCMS: m/z=618.98(M+H⁺); retention time=1.00 minutes.

Example 435 6-Bromo-3,4-dihydro-1H-quinoxalin-2-one

5-bromo-2,3-diaminopyridine (2.0 g, 10.6 mmol) and glyoxylic acidmonohydrate (1.23 g, 13.4 mmol) were combined in water (55 mL),sonicated for 10 minutes and stirred overnight. The product wasfiltered, washed with water (5×100 mL) and dried under vacuum to afford2.214 g of crude product. To a suspension of this material in methanol(100 mL) was added NaBH₄ (1.0 g, 26.3 mmol) with periodic cooling in anice water bath to maintain reaction temperature below 35° C. Afterstirring for 4 hours, the reaction was quenched with 6N HCl (20 mL) andthe resulting mixture stirred overnight. The mixture was warmed to 50°C. for 0.5 hour before removing volatile solvents by rotary evaporation.After adjusting the pH of the aqueous reside to 8 by the addition of 10NNaOH, the product was removed by filtration and washed with water (5×50mL) to give the title compound (1.985 g, 82%). m.p. 265° C. (dec),¹H-NMR (DMSO-d₆, 400 MHz) δ 10.47 (s, 1H), 7.65 (d, J=2.1 Hz, 1H),7.01-6.99 (m, 2H), 3.94 (s, 2H).

Example 4367-Bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one

To a solution of 6-bromo-3,4-dihydro-1H-quinoxalin-2-one (228 mg, 1.00mmol) in DMF (10 mL) was added NaH (40 mg of a 60% dispersion in mineraloil, 1.00 mmol) and the resulting mixture sonicated for 5 minutes. Afterstirring at room temperature for 20 minutes,2-chloro-3,6-difluorobenzylbromide (242 mg, 1.00 mmol) was added and themixture was stirred for 20 minutes. Solvent was reduced ˜90% and theresidue was triturated with ether (3×1 mL) and water (2×2 mL) to givethe title compound (275 mg, 71%). m.p. 214-216° C. (dec); LCMS:m/z=388/390/392 (M+H⁺); ¹H-NMR (DMSO-d₆, 400 MHz) δ 7.73 (s, 1H),7.47-7.42 (m, 1H), 7.35 (s, 1H), 7.32-7.26 (m, 1H), 7.11 (s, 1H), 5.24,(s, 2H), 4.01 (s, 2H).

Example 4371-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one

A mixture of7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one(42 mg, 0.11 mmol),1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine(40 mg, 0.13 mmol), palladium (II) acetate (4 mg) and triphenylphosphine(14 mg) in n-propanol (1.0 mL) was degassed with argon while adding a1.26 M aqueous solution of Na₂CO₃ (0.12 mL) followed by water (0.38 mL).This mixture was heated in a microwave for 10 minutes at 130° C., cooledto room temperature and extracted into CH₂Cl₂. The organic phase waspassed through a plug of Na₂SO₄, absorbed onto florisil and evaporatedto dryness. This material was purified by silica gel chromatography byeluting with increasing amounts of 5% NH₄OH/methanol in dichloromethane.The isolated material was recrystallized from methanol to give the titlecompound (15.4 mg, 29%). m.p. 235-236° C. (dec); LCMS: m/z=485/487(M+H⁺); ¹H-NMR (CDCl3-d₆, 400 MHz) δ 8.22 (d, J=2.4 Hz, 1H), 7.89 (d,J=2.4 Hz, 1H), 7.49-7.46 (m, 1H), 7.16 (s, 1H), 7.15-7.06 (m, 1H),7.05-6.93 (m, 1H), 6.69 (d, J=8.8, 1H), 5.43, (s, 2H), 4.81 (s, 1H),4.24 (s, 2H), 3.61-3.59 (m, 4H), 2.55-2.52 (m, 4H), 2.36 (s, 3H).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application and thescope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A compound of Formula I

or a pharmaceutically acceptable salt form thereof, wherein: A is N; Xis chosen from -L²G¹L³G²L⁴R⁷ and R⁸; L¹ is—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂—C₀₋₃-alkyl-, or—C₁₋₆-alkyl-; R¹ is an optionally mono- or polysubstituted group chosenfrom aryl and heteroaryl, wherein the substituents may be identical ordifferent and are chosen from halogen, —NO₂, —OR²⁰, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²⁰R²¹, —NR²⁰R²¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, aryl,heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen,—S(═O)_(n)R²⁰, —S(═O)₂NR²⁰R²¹, —OCH₂F, —OCHF₂, —OCF₃, —NHOH, —OC(═O)R²⁰,—OC(═O)NR²⁰R²¹, —NR²⁰C(═O)R²¹, —NR²⁰C(═O)OR²¹, and —SCF₃; R² and R³ areindependently chosen from H, OH, and C₁₋₆-alkyl, or R² and R³ togetherform a carbonyl group; R⁴ and R⁵ are independently chosen from H andC₁₋₆-alkyl, or R⁴ and R⁵ together form a carbonyl group; R⁶ is chosenfrom H and C₁₋₆-alkyl; L² is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O), —C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR³⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR³⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR³⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-, or—C₂₋₃-alkynyl-; G¹ is a bond, or an optionally mono- or polysubstitutedgroup chosen from aryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, andheteroaryl, wherein the substituents may be identical or different andare chosen from halogen, —NO₂, —OR⁴⁰, —C(═O)R⁴⁰, —C(═O)OR⁴⁰,—C(═O)NR⁴⁰R⁴¹, —NR⁴⁰R⁴¹, C₁₋₃-alkyl, C₁₋₃-haloalkyl, aryl, heteroaryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, pseudohalogen, —S(═O)_(n)R⁴⁰,—S(═O)₂NR⁴⁰R⁴¹, —OCH₂F, —OCHF₂, —OCF₃, —NHOH, —OC(═O)R⁴⁰,—OC(═O)NR⁴⁰R⁴¹, —NR⁴⁰C(═O)R⁴¹, —NR⁴⁰C(═O)OR⁴¹, and —SCF₃; L³ is a bond,—C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-,—C₂₋₃-alkenyl-, or —C₂₋₃-alkynyl-; G² is a bond, or an optionally mono-or polysubstituted group chosen from aryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, and heteroaryl, wherein the substituents may beidentical or different and are chosen from halogen, —NO₂, —OR⁶⁰,—C(═O)R⁶⁰, —C(═O)OR⁶⁰, —C(═O)NR⁶⁰R⁶¹, —NR⁶⁰R⁶¹, C₁₋₃-alkyl,C₁₋₃-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl,pseudohalogen, —S(═O)_(n)R⁶⁰, —S(═O)₂NR⁶⁰R⁶¹, —OCH₂F, —OCHF₂, —OCF₃,—NHOH, —OC(═O)R⁶⁰, —OC(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)R⁶¹, —NR⁶⁰C(═O)OR⁶¹, and—SCF₃; L⁴ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)_(n)—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-S(═O)₂NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-NR⁷⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-O—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-, or—C₂₋₃-alkynyl-; R⁷ is an optionally mono- or polysubstituted groupchosen from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl, wherein thesubstituents may be identical or different and are chosen from halogen,—NO₂, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹, C₁₋₆-alkyl,C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl,pseudohalogen, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCH₂F, —OCHF₂, —OCF₃,—NHOH, —OC(═O)R⁸⁰, —OC(═O)NR⁸⁰R⁸¹, —NR⁸⁰C(═O)R⁸¹, —NR⁸⁰C(═O)OR⁸¹,—SiR⁸⁰R⁸¹R⁸² and —SCF₃; R⁸ is chosen from H, halogen, CN, and C(═O)OH;R¹⁰, R²⁰, R²¹, R³⁰, R⁴⁰, R⁴¹, R⁵⁰, R⁶⁰, R⁶¹, R⁷⁰, R⁸⁰, R⁸¹, and R⁸² ateach occurrence are independently chosen from H, C₁₋₆-alkyl,C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl, andheterocycloalkyl; and n is 0, 1, or 2; provided that when L¹ is —C(═O)—and R¹ is phenyl, R⁸ is not or Br.
 2. A compound as defined in claim 1,wherein L¹ is —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, or—C₀₋₃-alkyl-S(═O)₂—C₀₋₃alkyl-.
 3. A compound as defined in claim 1,wherein L¹ is —C₁₋₆-alkyl-.
 4. A compound as defined in claim 1, whereineach R¹ substituent is independently chosen from halogen,—C(═O)—C₁₋₆-alkyl, C₁₋₃-haloalkyl, cyano, and —OCF₃.
 5. A compound asdefined in claim 1, wherein R² and R³ are independently chosen from Hand C₁₋₆-alkyl, or R² and R³ together form a carbonyl group.
 6. Acompound as defined in claim 1, wherein R⁴ and R⁵ are H.
 7. A compoundas defined in claim 1, wherein R⁶ is H.
 8. A compound as defined inclaim 1, wherein X is -L²G¹L³G²L⁴R⁷.
 9. A compound as defined in claim8, wherein L² is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—S(═O)_(n)—C₀₋₃-alkyl-, —C(═O)NR³⁰—C₀₋₃-alkyl-, —S(═O)₂NR³⁰—C₀₋₃-alkyl-,—C(═O)O—C₀₋₃-alkyl-, —CH₂—OC(═O)NR³⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-OC(═O)NR³⁰—CH₂—, —CH₂—NR³⁰—C₀₋₃-alkyl-, —CH₂—O—C₀₋₃-alkyl-,—CH₂—OC(═O)—C₀₋₃alkyl-, —CH₂—NR¹⁰C(═O)—C₀₋₃-alkyl-,—CH₂—NR¹⁰S(═O)₂—C₀₋₃-alkyl-, —C₁₋₃-alkyl-, —C₂₋₃-alkenyl-, or—C₂₋₃-alkynyl-.
 10. A compound as defined in claim 9, wherein L² is abond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-, —C(═O)NR³⁰—C₀₋₃-alkyl-,—C(═O)O—C₀₋₃-alkyl-, or —C₂₋₃-alkynyl-.
 11. A compound as defined in 8,wherein G¹ is a bond, or an optionally mono- or polysubstituted groupchosen from aryl, heterocycloalkyl, and heteroaryl.
 12. A compound asdefined in claim 8, wherein L³ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-S(═O)₂NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, —C₀₋₃-alkyl-OC(═O)NR⁵⁰—C₀₋₃-alkyl-,—C₀₋₃-alkyl-NR⁵⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-.
 13. A compound as defined in claim 8, wherein G² is abond, or an optionally mono- or polysubstituted group chosen from aryl,heterocycloalkyl, and heteroaryl.
 14. A compound as defined in claim 8,wherein L⁴ is a bond, —C₀₋₃-alkyl-C(═O)—C₀₋₃-alkyl-,—C₀₋₃-alkyl-C(═O)NR⁷⁰—C₀₋₃-alkyl-, —C₀₋₃-alkyl-C(═O)O—C₀₋₃-alkyl-, or—C₁₋₃-alkyl-.
 15. A compound as defined in claim 8, wherein R⁷ is anoptionally mono- or polysubstituted group chosen from C₁₋₆-alkyl, aryl,C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl.
 16. A compound asdefined in claim 15, wherein each R⁷ substituent is independently chosenfrom halogen, —OR⁸⁰, —C(═O)R⁸⁰, —C(═O)OR⁸⁰, —C(═O)NR⁸⁰R⁸¹, —NR⁸⁰R⁸¹,C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl, C₃₋₁₀-cycloalkyl,heterocycloalkyl, cyano, —S(═O)_(n)R⁸⁰, —S(═O)₂NR⁸⁰R⁸¹, —OCF₃, and—SiR⁸⁰R⁸¹R⁸².
 17. A compound as defined in claim 8, wherein at least oneof G¹ and R⁷ is an optionally mono- or polysubstituted group chosen fromaryl, C₃₋₁₀-cycloalkyl, heterocycloalkyl, and heteroaryl.
 18. A compoundas defined in claim 1, wherein said compound is1-(2-chloro-3,6-difluorobenzyl)-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;4-[1-(2-chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester;4-[1-(2-chloro-3,6-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid;1-(2-chloro-3,6-difluorobenzyl)-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid ethyl ester;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid; 1-benzyl-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)benzamide;S-1-benzyl-7-[4-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-morpholin-4-yl-propyl)benzamide;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(4-dimethylaminobutyl)benzamide;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(6-dimethylaminohexyl)benzamide;S-1-benzyl-7-[3-(2[-(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;3-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino-ethyl)benzamide;1-benzyl-7-[3-(pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;7-(4-acetylphenyl)-1-benzyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;3-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzamide;1-benzyl-7-(4-methanesulfonyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;1-benzyl-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;1-benzyl-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide;5-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile;5-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carboxylicacid ethyl ester;3-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid methyl ester;3-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoicacid; 1-benzyl-7-pyridin-3-yl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;4-(1-benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acidethyl ester;4-(1-benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid;[4-(1-benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-methylpiperazin-1-yl)methanone;[4-(1-benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-((S)-2-pyrrolidinylmethylpyrrolidin-1-yl)methanone;[4-(1-benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;phenyl-(7-pyridin-3-yl-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone;4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acidethyl ester; 2-pyrrolidin-1-yl-ethanesulfonicacid[4-(1-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide;2-pyrrolidin-1-yl-ethanesulfonicacid[4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide;2-(4-methylpiperazin-1-yl)-ethanesulfonicacid[4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide;2-pyrrolidin-1-yl-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;2-[ethyl-((S)-1-pyrrolidin-1-ylmethyl-propyl)-amino]-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;2-morpholin-4-yl-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;2-pyrrolidin-1-yl-ethanesulfonicacid{4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino-ethyl)benzamide;4-(1-benzoyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-dimethylamino-propyl)benzamide;{7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}phenylmethanone;4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester;4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid;1-(2,5-difluorobenzyl)-7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin-1-yl-ethyl)benzamide;1-(2,5-difluorobenzyl)-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;1-(2,5-difluorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylicacid{4-[1-(2,5-difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester;4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid;{4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone;{4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;{4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;{4-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-morpholin-4-yl-methanone;1-(2,5-difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2,5-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;5-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carbonitrile;5-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carboxylicacid;5-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinicacid ethyl ester;5-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinicacid;1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid ethyl ester;{5-[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2-yl}morpholin-4-yl-methanone;[1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-methylpiperazin-1-yl)methanone;1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid[2(4-methylpiperazin-1-yl)ethyl]amide;7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-{4-[1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone;7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;(4-methylpiperazin-1-yl)-{4-[1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone;(2,5-difluorophenyl)-{7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-methanone;(2,5-difluorophenyl)-{7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-methanone;1-(2,5-difluorobenzyl)-3,3-dimethyl-7-[4-((S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;1-(2,5-difluorobenzyl)-3,3-dimethyl-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;{4-[1-(2,5-difluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone;{4-[1-(2,5-difluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;{4-[1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;{4-[1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methanone;1-(2-chloro-3,6-difluorobenzyl)-7-(3-chloro-2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(3-fluoro-2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(3,5-dimethyl-isoxazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;{4-[1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;1-(2-chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)-pyrimidin-5-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyrimidin-5-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;2-phenyl-1-{7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}-ethanone;2-(2,5-difluorophenyl)-1-{7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}ethanone;2-(2,5-difluorophenyl)-1-{7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl}ethanone;{4-[1-(5-chloro-2-trifluoromethylbenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;1-(5-chloro-2-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-5-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2,5-difluorobenzenesulfonyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-benzenesulfonyl-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chlorobenzenesulfonyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4tetrahydropyrido[2,3-b]pyrazine;1-(2,5-dichlorobenzyl)-7-(2-methoxypyrimidin-5-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;4-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester;1-(2,5-dichlorobenzyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine,{4-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-methylpiperazin-1-yl)methanone;1-(2,6-dichlorobenzyl)-7-pyridin-3-yl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;1-(2,6-dichlorobenzyl)-7-pyridin-3-yl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;4-[1-(2,6-dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester;4-[1-(2,6-dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid;S-1-(2,6-dichlorobenzyl)-7-[4-((2-pyrrolidin-1-yl)methylpyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;4-[1-(2,6-dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin-1-yl-ethyl)benzamide;4-[1-(2,6-dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(6-dimethylaminohexyl)benzamide;4-[1-(2,6-dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(4-dimethylaminobutyl)benzamide;7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1-[1-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;S-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}-(4-{1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(4-methylpiperazin-1-yl)-(4-{1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;S-(4-{1-[1-(2,5-difluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;1-[1-(2,5-difluorophenyl)ethyl]-7-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;S-(4-{1-[1-(2,5-difluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;1-(2,5-dichlorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;S-1-(2,5-dichlorobenzyl)-7-[4-(2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;S-{4-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;{4-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;1-(2,6-dichlorobenzyl)-7-[4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl]-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one;{4-[1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;{4-[1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-{2-[(pyrrolidin-1-yl)methyl]pyrrolidin-1-yl}methanone;7-(6-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2,5-dichlorobenzyl)-7-(6-pyrrolidin-1-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;7-(2-chloropyridin-4-yl)-1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;{3-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamicacid tert-butyl ester;3-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine;{3-[1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamicacid tert-butyl ester;3-[1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine;N-{3-[1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}-2-dimethylamino-acetamide;{3-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}-dimethylamine;1-(2,5-dichlorobenzyl)-7-[3-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)prop-1-ynyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-[1-(2-chloro-3,6-difluorophenyl)ethyl]-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2,5-dichlorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-[3-fluoro-2-(trifluoromethyl)benzyl]-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(2-pyrrolidin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;5-[1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2-ylamine;1-(2-chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2,5-dichlorobenzyl)-4-methyl-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-[1-(3-methylbutyl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-(2-chloro-3,6-difluorobenzyl)-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid;(2-{4-[1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyrazol-1-yl}ethyl)dimethylamine;1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine;1-[4-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}pyridin-2-yl)piperazin-1-yl]ethanone;1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine;1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine;1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;{1-[(5-chloro-2-trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}piperidin-1-yl-methanone;{1-[(5-chloro-2-trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-(4-methoxy-piperidin-1-yl)methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperazin-1-yl)-methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-pyrimidin-2-yl-piperazin-1-yl)-methanone;[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;1-{1-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperidin-4-yl}-1,3-dihydrobenzoimidazol-2-one;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-methoxyphenyl)piperazin-1-yl]methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperidin-1-yl)methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(3,4-dichlorophenyl)-piperazin-1-yl]methanone;(4-benzhydrylpiperazin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;(4-benzylpiperidin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;8-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4-methoxybenzyl)piperazin-1-yl]methanone;(4-benzoylpiperazin-1-yl)-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]methanone;[4-(3-chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-pyridin-2-yl-ethyl)amide;4-{[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]amino}piperidine-1-carboxylicacid ethyl ester;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (1-benzyl-piperidin-4-yl)amide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2,2-diphenylethyl)amide;1-{4-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin-1-yl}ethanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 3-chlorobenzylamide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 4-(trifluoromethoxy)benzylamide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-morpholin-4-yl-piperidin-1-yl)methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-thiophen-2-yl-ethyl)amide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid benzhydrylamide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (pyridin-4-ylmethyl)amide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (pyridin-3-ylmethyl)amide;2-{4-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin-1-yl}-N-isopropylacetamide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 3,5-bis-(trifluoromethyl)benzylamide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid[2-(4-sulfamoylphenyl)ethyl]amide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-phenylthiazol-4-yl-methyl)amide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]morpholin-4-yl-methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (naphthalen-1-yl-methyl)amide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid indan-1-ylamide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid benzylamide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4-methoxyphenyl)piperazin-1-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid cyclohexylamide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (biphenyl-4-ylmethyl)amide;[4-(4-chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (2-phenoxyethyl)amide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid phenethyl-amide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid (tetrahydrofuran-2-yl-methyl)amide;[4-(4-chlorobenzyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 2-chloro-benzylamide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-(trifluoromethyl)phenyl)piperazin-1-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 4-methoxybenzylamide;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid indan-2-ylamide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenethyl-piperazin-1-yl)methanone;[4-(2-chlorophenyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;[(4-cyclohexylmethyl)piperazin-1-yl]-[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid 4-sulfamoyl-benzylamide;[1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2-pyridin-3-yl-pyrrolidin-1-yl)methanone;(4-{1-[5-chloro-2(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-morpholin-4-yl-piperidin-1-yl)methatone;(4-{1-[5-chloro-2(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thiazol-2-yl-piperazin-1-yl)methatone;3,6-difluoro-2-[7-(6-morpholin-4-yl-pyridin-3-yl)-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-ylmethyl]benzonitrile;7-(6-morpholin-4-yl-pyridin-3-yl)-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine;1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylicacid[4-(dimethylamino)butyl]amide;4-{1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid ethyl ester;4-{1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoicacid;4-[1-(2-chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid ethyl ester;4-[1-(2-chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoicacid;{4-[1-(2-chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)methanone;N-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)acetamide;(4-pyrrolidin-1-yl-piperidin-1-yl)-(4-{1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperazin-1-yl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin-1-yl)methanone;[4-(4-chlorophenyl)-piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;1-[1-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-1,3-dihydrobenzoimidazol-2-one;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin-1-yl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(1H-indol-3-yl)piperidin-1-yl]methanone;(4-benzhydrylpiperazin-1-yl)-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(4-benzylpiperidin-1-yl)-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-1-yl]methanone;8-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-ylpiperazin-1-yl)methanone;[4-(4-chlorobenzyl)piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-1-yl]methanone;(4-benzoylpiperazin-1-yl)-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-furo[3,2-c]pyridin-4-ylpiperazin-1-yl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]methanone;4-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoylamino)piperidine-1-carboxylicacid ethyl ester;N-(1-benzylpiperidin-4-yl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(1-methylpiperidin-4-yl)benzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzamide;N-[3,5-bis(trifluoromethyl)benzyl]-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;N-benzhydryl-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-4-ylmethylbenzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-3-ylmethylbenzamide;2-[4-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]-N-isopropylacetamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)morpholin-4-ylmethanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-naphthalen-1-ylmethylbenzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-1-ylbenzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3-methoxyphenyl)piperazin-1-yl]methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-cyclohexylbenzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methanesulfonylbenzyl)benzamide;N-(2-chlorobenzyl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;N-(4-chlorobenzyl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;N-(3-chlorobenzyl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(3-methoxybenzyl)benzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzamide;N-benzyl-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;[4-(3-chlorophenyl)piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-2-ylbenzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenethylpiperazin-1-yl)methanone;[4-(2-chlorophenyl)piperazin-1-yl]-(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;N-(1-benzylpyrrolidin-3-yl)-3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(cyclohexylmethyl)piperazin-1-yl]methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-morpholin-4-ylpiperidin-1-yl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-((S)-2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)methanone;(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2-pyridin-3-ylpyrrolidin-1-yl)methanone;3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxybenzyl)-N-methylbenzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperazin-1-yl)methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin-1-yl)methanone;[4-(4-chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;1-[1-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-1,3-dihydrobenzoimidazol-2-one;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin-1-yl)methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(1H-indol-3-yl)piperidin-1-yl]methanone;(4-benzhydrylpiperazin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(4-benzylpiperidin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-1-yl]methanone;8-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)methanone;[4-(4-chlorobenzyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-1-yl]methanone;(4-benzoylpiperazin-1-yl)-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-furo[3,2-c]pyridin-4-ylpiperazin-1-yl)methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-pyridin-2-yl-ethyl)benzamide;4-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoylamino)piperidine-1-carboxylicacid ethyl ester;N-(1-benzylpiperidin-4-yl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide;1-[4-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]ethanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(1-methylpiperidin-4-yl)benzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl]methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[4-(trifluoromethyl)benzyl]benzamide;N-[3,5-bis(trifluoromethyl)benzyl]-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-thiophen-2-yl-ethyl)benzamide;N-benzhydryl-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-4-ylmethylbenzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-pyridin-3-ylmethylbenzamide;2-[4-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoyl)piperazin-1-yl]-N-isopropylacetamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-1-yl]methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxyethyl)benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)morpholin-4-ylmethanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-naphthalen-1-ylmethylbenzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-1-ylbenzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone;N-(2-chlorobenzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;N-(4-chlorobenzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;N-(3-chloro-benzyl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-phenethylbenzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(3-methoxybenzyl)benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzamide;N-benzyl-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;[4-(3-chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-indan-2-ylbenzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(4-phenethylpiperazin-1-yl)methanone;N-biphenyl-4-ylmethyl-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;[4-(2-chlorophenyl)piperazin-1-yl]-(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;N-(1-benzylpyrrolidin-3-yl)-4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-[4-(cyclohexylmethyl)piperazin-1-yl]methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-((S)-2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)methanone;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(2-pyridin-3-yl-pyrrolidin-1-yl)methanone;4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2-methoxybenzyl)-N-methylbenzamide;(4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-(1,3-dihydroisoindol-2-yl)methanone;{4-[1-(5-chloro-2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-phenyl}-(spiro[isobenzofuran-1(3H),4′-piperidine]-1-yl)methanone; or1-(2-chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one;or a pharmaceutically acceptable salt form thereof.
 19. A pharmaceuticalcomposition comprising a compound as defined in claim 1 and apharmaceutical acceptable carrier, diluent, or excipient.